CN102174076A - Compounds for proteasome enzyme inhibition - Google Patents
Compounds for proteasome enzyme inhibition Download PDFInfo
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- CN102174076A CN102174076A CN201110037869XA CN201110037869A CN102174076A CN 102174076 A CN102174076 A CN 102174076A CN 201110037869X A CN201110037869X A CN 201110037869XA CN 201110037869 A CN201110037869 A CN 201110037869A CN 102174076 A CN102174076 A CN 102174076A
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- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/10—Tetrapeptides
- C07K5/1002—Tetrapeptides with the first amino acid being neutral
- C07K5/1016—Tetrapeptides with the first amino acid being neutral and aromatic or cycloaliphatic
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- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/08—Tripeptides
- C07K5/0802—Tripeptides with the first amino acid being neutral
- C07K5/0812—Tripeptides with the first amino acid being neutral and aromatic or cycloaliphatic
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/08—Tripeptides
- C07K5/0827—Tripeptides containing heteroatoms different from O, S, or N
Abstract
Peptide-based compounds including heteroatom-containing, three-membered rings efficiently and selectively inhibit specific activities of N-terminal nucleophile (Ntn) hydrolases. The activities of those Ntn having multiple activities can be differentially inhibited by the compounds described. For example, the chymotrypsin-like activity of the 20S proteasome may be selectively inhibited with the inventive compounds. The peptide-based compounds include at least three peptide units, an epoxide or aziridine, and functionalization at the N-terminus. Among other therapeutic utilities, the peptide-based compounds are expected to display anti-inflammatory properties and inhibition of cell proliferation.
Description
The application is that the national applications that is entitled as " compound that is used for arrestin enzyme body enzyme " submitted on April 14th, 2005 number is the dividing an application of application for a patent for invention of 200580019845.4 (PCT/US2005/012740).
Technical field
The present invention relates to be used for the Compounds and methods for of inhibitory enzyme.Particularly, the present invention relates to the methods of treatment that suppresses based on enzyme.
Background of invention
In eukaryote, mainly by the degraded of ubiquitin (ubiquitin) approach mediating protein, wherein Jiang Xie target protein is connected with 76 amino acid whose polypeptide ubiquitin.In case become target, ubiquitin protein just becomes the substrate of 26S proteasome, and the 26S proteasome is many catalysiss proteolytic enzyme (Multicatalytic protease), by its three kinds of main proteolytic activity protein is cut into small peptide.Though the degraded of proteasome mediation has general function in the intracellular protein conversion, in such as a plurality of processes such as the presenting of I class major histocompatibility complex (MHC), apoptosis, cytodifferentiation and NF-kB activations, also play a significant role.
The 20S proteasome is cylindric many catalysiss proteolytic enzyme complex body of 700kDa, contain 28 subunits that constitute 4 rings, the presenting of cell cycle regulation, I class major histocompatibility complex, transfer and die, play an important role in the transduction of antigen processing, NF-kB activation and short scorching signal.In yeast and other eukaryotic cell, 7 different α subunits constitute outer shroud, ring in 7 different β subunits constitute.The α subunit is as the binding site of 19S (PA700) and 11S (28PA) adjusting complex body, and the endoproteinase of two β subunit ring formations is separated the physical barriers in chamber.Therefore think that this proteasome exists with 26S particle (" 26S proteasome ") form in vivo.In vivo test shows, to the inhibition of the proteasome of 20S form easily with relevant to the inhibition of 26S proteasome.During forming, particle, make the aminoterminal threonine residues that is used as the catalysis nucleophile come out to the cutting of the former sequence of aminoterminal β subunit (prosequence).So, to be responsible for the subunit of catalytic activity in the proteasome aminoterminal nucleophilic residues is processed, these subunits belong to N end nucleophilic (Ntn) hydrolase family (wherein nucleophilic N end residue is such as nucleophilic compositions such as halfcystine, Serine, Threonines).This family comprises, for example, and penicillin G acylase (PGA), penicillin v acyltransferase (PVA), glutamine PRPP amido saccharase and bacterium glycosyl asparaginase.Except the β subunit that omnipresence is expressed, more high vertebrates also has 3 gamma-interferon induction type β subunits (LMP7, LMP2 and MECL1), substitutes its normal corresponding subunit X, Y and Z respectively, has changed the catalytic activity of proteasome like this.By using different peptide substrates, three kinds of main proteolytic activity of eukaryote 20S proteasome are defined as: chymotrypsin-like activity (CT-L), after big hydrophobic residue, cut; Trypsin-like activity (T-L) is cut after alkaline residue; And peptidyl glutamyl hydrolase polypeptide activity (PGPH), after acidic residues, cut.Proteasome also has two other minor feature activity: the BrAAP activity, after branched-chain amino acid, cut; The SNAAP activity is cut after little neutral amino acids.As if the major protein enzymolysis activity of proteasome causes by different catalytic site, because the exchange of point mutation in the inhibitor, β subunit and gamma-interferon induction type β subunit makes these active various degree change take place.
More existing example small molecules are used for the activity of arrestin enzyme body; But these compounds generally lack probes into and develops the necessary specificity of proteasome function, stability or potentiality on cell and molecular level.Therefore, need that synthetic site-specific nature is improved, stability and solvability improve, the micromolecular inhibitor that potentiality are enhanced, thus can on cell and molecular level, the function to proteasome probe into.
Summary of the invention
The present invention relates to be called as peptide α ', β '-epoxide and peptide α ', the analogue of the molecular species of β '-ethylenimine and prodrug.Parent molecule is believed to be effectively, irreversibly and optionally combines with N end nucleophilic (Ntn) lytic enzyme, can the specificity inhibition have the given activity of the enzyme of many catalytic activitys.
Once thought proteasome protein that only handle sex change and malfolding, recognize that now it has constituted by relying on the degraded mode of signal, regulates the proteolysis mechanism of the level of multiple intracellular protein.Therefore, people can specificity disturb the reagent of proteasome and other Ntn hydrolytic enzyme activities for differentiating, thereby nourish great interest used as the probe of the effect of these enzymes of research in biological processing.Here analogue and the prodrug to the compound that is used for target Ntn lytic enzyme be described, synthetic and research.The peptide epoxide and the peptide ethylenimine of the proteasome activity that can effectively, optionally and irreversibly suppress specific are disclosed, and claimed to it.
Be different from some other inhibitor based on peptide, this described peptide epoxide of expectability and peptide ethylenimine fully do not suppress the proteolytic enzyme of non-proteasome during up to 50 μ M in concentration, as trypsinase, Quimotrase, cathepsin B, papoid, Calpain.Under higher concentration, can observe restraining effect, if but inhibitor only with substrate competition, expect that this restraining effect is emulative and reversible.Also expect the activation that peptide epoxide that this is novel and peptide ethylenimine can suppress NF-κ B, the p53 level in the stabilized cell culture.In addition, expect that these compounds have anti-inflammatory activity.Therefore, these compounds can be used as unique multi-functional molecular probe, to probe into the function of Ntn enzyme in normal biological procedures and pathological process.
On the one hand, the invention provides and comprise inhibitor analogue and the prodrug that contains heteroatomic triatomic ring.When described inhibitor exist concentration to be lower than about 50 μ M the time, these inhibitor can suppress the catalytic activity of N end nucleophilic lytic enzyme (for example 20S proteasome or 26S proteasome).For the 20S proteasome, specific hydrolase inhibitor exists concentration when being lower than about 5 μ M at it, the chymotrypsin-like activity that suppresses the 20S proteasome, and exist concentration when being lower than about 5 μ M when it, do not suppress the trypsin-like activity or the PGPH activity of 20S proteasome.Hydrolase inhibitor can for, for example, peptide α ', β '-epoxy ketone or α ', β '-ethylenimine ketone, this peptide can be tetrapeptides.This tetrapeptide can comprise branch or unbranched side chain, as hydrogen, C
1-6Alkyl, C
1-6Hydroxyalkyl, C
1-6Alkoxyalkyl, aryl, C
1-6Aralkyl, C
1-6Alkylamide, C
1-6Alkylamine, C
1-6Carboxylic acid, C
1-6Carboxylicesters, C
1-6Alkyl sulfhydryl or C
1-6Alkyl thioether, for example isobutyl-, 1-naphthyl, phenmethyl and 2-styroyl.Here Ding Yi α ', β '-epoxy ketone or α ', the α '-carbon in β '-ethylenimine ketone can be chiral carbon atom, for example the carbon of (R) or beta comfiguration.
On the other hand, the invention provides pharmaceutical composition, comprise a kind of pharmaceutically acceptable carrier and a kind of neurodegenerative disease (as alzheimer ' Mo Ershi disease), muscular dystrophy (muscle-wasting diseases), cancer, chronic infectious disease, heating, useless hydrolase inhibitor analogue or prodrug and other material of using the pharmacy effective dose of (muscle disuse), denervation, nerve injury, fasting and Ia illness of muscle of improving.
On the other hand, the invention provides anti-inflammatory composition.
On the other hand, the invention provides the method that is used for following aspect: suppress or alleviate individual HIV to infect; Influence the viral gene expression level in the individuality; Change the kind of the antigen peptide that proteasome produced in the organism; Determine the adjusting whether cell, that grow or physiological process in the organism or output are subjected to the proteolytic activity of specific Ntn lytic enzyme; Alzheimer ' Mo Ershi disease to individuality is treated; Reduce the degradation speed of mytolin in the cell; Reduce the degradation speed of intracellular protein in the cell; Reduce the proteic degradation speed of p53 in the cell; Suppress the growth of the relevant cancer of p53 in the individuality; Suppress intracellular antigen presentation; Immunity system to individuality is prevented; Suppress the I κ B-α degraded in the organism; Reduce cell, muscle, organ or individual intravital NF-κ B content; Influence depends on the eukaryotic cell cycle of cyclin; Proliferative disease to individuality is treated; Influencing the dependent oncoprotein of intracellular protease body regulates; The growth of cancers that treatment is individual; P53 dependency in the treatment individuality is transferred and is died; The protein of N end nucleophilic lytic enzyme processing in the screening cell.In these methods each comprises the composition of individuality, cell, tissue, organ or organism being used the hydrolase inhibitor that comprises here to be disclosed of significant quantity, or individuality, cell, tissue, organ or organism are contacted with the composition of significant quantity.
Other features and advantages of the present invention will obtain embodying in the following detailed description and claim.
Detailed Description Of The Invention
The present invention relates to compound as enzyme inhibitors.These compounds are common to holds the enzyme with nucleophilic group to suppress to N.For example, enzyme inhibitors described here can successfully suppress to contain the enzyme of N terminal amino acid (as Threonine, Serine or halfcystine etc.) of side chain band nucleophile or the activity of enzyme subunit.Enzyme inhibitors described here also can successfully be suppressed at its N end and have the enzyme of non-amino acid nucleophilic group (for example protecting group or carbohydrate) or the activity of enzyme subunit.
Though limited the epoxide functional group formation covalency adducts of the N end nucleophile that it is believed that this Ntm and enzyme inhibitors described here without any concrete action principle.For example think that in the β of 20S proteasome 5/Pre2 subunit N end Threonine and peptide epoxide or peptide ethylenimine (for example hereinafter described compound) reaction irreversibly form morpholino adducts or Piperazino adducts.The formation of this adducts relates to the open loop cracking of epoxide or ethylenimine.
Comprise and the embodiment of this kind of α ' carbon bonded group in, the stereochemistry of α '-carbon (forming the carbon of the part of epoxide or ethylenimine ring) can be (R) or (S).The present invention part is based on the structure-function information that is disclosed here, this information indicating following preferred stereochemistry relation.Note, preferred compound can contain some stereocenters, on stereocenter has-down (or β-α, wherein the β that draws here is above the page) or the relation of demonstration (R)-(S) (not needing each stereocenter in the compound all to meet described optimal way).Some preferred embodiment in, the stereochemistry of α ' carbon is (R), that is, the X atom is β, or is positioned at the top of planes of molecules.
For stereochemistry, follow the Cahn-Ingold-Prelog rule that is used for determining the absolute stereo chemistry.Such as organic chemistry (Fox and Whitesell; Jones and Charles Bartlett press, Boston, MA (1994); 5-6 joint, the 177-178 page or leaf, whole here with reference to this joint content) etc. these rules are described.Peptide can have the repetition backbone structure, stretches out side chain from main chain unit.Usually, each main chain unit has an associating with it side chain, although sometimes, this side chain is a hydrogen atom.In other embodiment, be not that each main chain unit all has an associating side chain.The peptide that is used for peptide epoxide or peptide ethylenimine has two or more main chain units.There is a 4-8 main chain unit in the active embodiment of chymotrypsin-like (CT-L) that some are used for arrestin enzyme body, and there is a 4-6 main chain unit in the preferred implementation that some are used for suppressing CT-L.
The side chain that stretches out from main chain unit can comprise natural aliphatic series or aromatic amino acid side chain, as the side chain of hydrogen (glycine), methyl (L-Ala), sec.-propyl (Xie Ansuan), sec-butyl (Isoleucine), isobutyl-(leucine), phenmethyl (phenylalanine) and formation proline(Pro).Side chain also can be other branch or unbranched aliphatic group or aromatic base, the derivative that replaces of ethyl, n-propyl, normal-butyl, the tertiary butyl and aryl for example is as 1-styroyl, 2-styroyl, (1-naphthyl) methyl, (2-naphthyl) methyl, (1-naphthyl) ethyl, 1-(2-naphthyl) ethyl, 2-(1-naphthyl) ethyl, 2-(2-naphthyl) ethyl and similar compounds.Aryl can further be branched or unbranched C
1-6Replacement such as alkyl or substituted alkyl, ethanoyl, or by other aryl or such as replacements such as substituted aryl such as benzoyls.Heteroaryl also can be used as side chain substituents.That heteroaryl comprises is nitrogenous, the aryl of oxygen and sulphur, as thienyl, benzothienyl, aphthothiophenes base, thianthrenyl, furyl, pyranyl, isobenzofuran-base, benzopyranyl, pyrryl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, indyl, purine radicals, quinolyl etc.
In some embodiments, can in peptide epoxide or peptide ethylenimine, introduce polar residues or charged residue.For example can introduce naturally occurring amino acid (as hydroxyl (Thr, Tyr, Ser) or sulfur-bearing (Met, Cys) amino acid) and such as non-essential amino acid such as taurine, carnitine, citrulline, Gelucystine, ornithine, nor-leucine and other amino acid.The side chain substituents that can also comprise the non-natural existence that contains alive part or polarity part, for example, the substituent C of this class that contains one or more hydroxyl, short chain alkoxyl group, thioether (sulfide), sulfo-, carboxyl, ester, phospho, amido or amino or replaced by one or more halogen atom
1-6Alkyl chain or C
6-12Aryl.Some preferred embodiment in, have at least one aryl in the side chain of peptide moiety.
In some embodiments, main chain unit is acid amides unit [NH-CHR-C (=O)-], and wherein R is a side chain.The ring-type secondary amino acid of other non-natural existence of naturally occurring proline(Pro) or one skilled in the art's approval is not got rid of in this appointment.
In the other embodiment, main chain unit is the combination of the alkylating acid amides unit of N (for example, N-methyl etc.), alkene analogue (one of them or more a plurality of amido linkage are replaced by ethylene linkage), tetrazolium analogue (wherein tetrazole ring is cis-configuration on main chain) or these main chain keys.In other embodiments, the amino acid alpha-carbon replaces through alpha-alkyl to be modified, for example, and aminoisobutyric acid.In the other embodiment, side chain is carried out the part modify, for example carry out Δ
EOr Δ
ZDehydrogenation is modified, and wherein has pair keys between the alpha atom of side chain and β atom, or for example carries out Δ
EOr Δ
ZCyclopropyl is modified, and wherein has cyclopropyl between the alpha atom of side chain and β atom.In the embodiment of employing amino acid group in addition, can use D-amino acid.Further embodiment can comprise the cyclisation of side chain chain linked to owner, disulfide linkage formations, lactan formation, azo bond and in " peptide and conformation restriction simulation, design " (Hruby and Boteju), " molecular biology and biotechnology: comprehensive desk reference book " (Robert A.Meyers volume, VCH press (1995), 658-664 page or leaf, here comprehensive reference) middle other modification of discussing.
In some embodiment, motif compound is that sequence number is the analogue or the prodrug of 09/569748 the disclosed compound of U. S. application, the whole content of this application is carried out comprehensive reference here.Suitable enzyme inhibitors analogue or prodrug can have structure or its pharmacy acceptable salt of formula (I),
Wherein each A independently is selected from C=O, C=S and SO
2, preferred C=O; Or
When adjacent with the Z that exists, A is optional to be covalent linkage;
L does not exist or is selected from C=O, C=S and SO
2, preferred L does not exist or is C=O;
M does not exist or is C
1-12Alkyl is preferably C
1-8Alkyl;
Q does not exist or is selected from O, NH and N-C
1-6Alkyl, preferred Q do not exist or are O or NH,
Most preferably Q does not exist or is O;
X is selected from O, NH and N-C
1-6Alkyl is preferably O;
Y does not exist or is selected from O, NH and N-C
1-6Alkyl, S, SO, SO
2, CHOR
10And CHCO
2R
10
Each Z independently is selected from O, S, NH and N-C
1-6Alkyl is preferably O; Or
When adjacent with the A that exists, Z is optional to be covalent linkage;
R
1, R
2, R
3And R
4Independently be selected from C separately
1-6Alkyl, C
1-6Hydroxyalkyl, C
1-6Alkoxyalkyl, aryl and C
1-6Aralkyl, any group wherein randomly (are comprised C by one or more acid amides, amine, carboxylic acid (or its salt), ester
1-5Alkyl ester and aryl ester), mercaptan or thioether substituting group replace;
R
5Be N (R
6) LQR
7
R
6, R
12, R
13And R
14Independently be selected from hydrogen, OH, C
1-6The group of alkyl and formula IV; Preferably, R
6Be selected from hydrogen, OH and C
1-6Alkyl, and R
12, R
13And R
14Independently be selected from hydrogen and C
1-6Alkyl (preferred hydrogen);
R
7Be selected from hydrogen, C
1-6Alkyl, C
1-6Thiazolinyl, C
1-6Alkynyl, aryl, C
1-6Aralkyl, heteroaryl, C
1-6Heteroaralkyl, R
8ZAZ-C
1-8Alkyl-, R
11Z-C
1-8Alkyl-, (R
8O) (R
9O) P (=O) O-C
1-8Alkyl-ZAZ-C
1-8Alkyl-, R
8ZAZ-C
1-8Alkyl-ZAZ-C
1-8Alkyl-, heterocyclic radical MZAZ-C
1-8Alkyl-, (R
8O) (R
9O) P (=O) O-C
1-8Alkyl-, (R
10)
2N-C
1-12Alkyl-, (R
10)
3N
+-C
1-12Alkyl-, heterocyclic radical M-, carbocylic radical M-, R
11SO
2C
1-8Alkyl-and R
11SO
2NH; Preferred C
1-6Alkyl, C
1-6Thiazolinyl, C
1-6Alkynyl, aryl, C
1-6Aralkyl, heteroaryl, C
1-6Heteroaralkyl, R
8ZA-C
1-8Alkyl-, R
11Z-C
1-8Alkyl-, (R
8O) (R
9O) P (=O) O-C
1-8Alkyl-ZAZ-C
1-8Alkyl-, (R
8O) (R
9O) P (=O) O-C
1-8Alkyl-, Z-C
1-8Alkyl-, R
8ZA-C
1-8Alkyl-ZAZ-C
1-8Alkyl-, heterocyclic radical MZAZ-C
1-8Alkyl-, (R
8O) (R
9O) P (=O) O-C
1-8Alkyl-, (R
10)
2N-C
1-8Alkyl-, (R
10)
3N
+-C
1-8Alkyl-, heterocyclic radical M-, carbocylic radical M-, R
11SO
2C
1-8Alkyl-and R
11SO
2NH, wherein each existence of Z and A is independently, is not covalent linkage; Or
R
6And R
7Common is C
1-6Alkyl-Y-C
1-6Alkyl, C
1-6Alkyl-ZAZ-C
1-6Alkyl, ZAZ-C
1-6Alkyl-ZAZ-C
1-6Alkyl, ZAZ-C
1-6Alkyl-ZAZ or C
1-6Alkyl-A forms ring thus; Preferred C
1-2Alkyl-Y-C
1-2Alkyl, C
1-2Alkyl-ZA-C
1-2Alkyl, A-C
1-2Alkyl-ZA-C
1-2Alkyl, A-C
1-3Alkyl-A or C
1-4Alkyl-A, wherein each existence of Z and A is independently, is not covalent linkage;
R
8And R
9Independently be selected from hydrogen, metallic cation, C
1-6Alkyl, C
1-6Thiazolinyl, C
1-6Alkynyl, aryl, heteroaryl, C
1-6Aralkyl and C
1-6Heteroaralkyl is preferably selected from hydrogen, metallic cation, C
1-6Alkyl, or R
8And R
9Common is C
1-6Alkyl forms ring thus;
Each R
10Independently be selected from hydrogen and C
1-6Alkyl is preferably C
1-6Alkyl; And
R
11Independently be selected from hydrogen, C
1-6Alkyl, C
1-6Thiazolinyl, C
1-6Alkynyl, carbocylic radical, heterocyclic radical, aryl, heteroaryl, C
1-6Aralkyl and C
1-6Heteroaralkyl;
R
15And R
16Independently be selected from hydrogen, C
1-6Alkyl, or R
15And R
16Common carbocyclic ring or the heterocycle that forms 3-6 unit; And R
17And R
18Independently be selected from hydrogen, metallic cation, C
1-6Alkyl and C
1-6Aralkyl, or R
17And R
18Common expression C
1-6Alkyl forms ring thus;
Condition is to work as R
6, R
12, R
13And R
14Be H or CH
3, and Q is not when existing, LR
7Not hydrogen, unsubstituted C
1-6Alkyl C=O, amino acid whose another chain, tertbutyloxycarbonyl (Boc), benzoyl (Bz), fluorenes-9-base methoxycarbonyl (Fmoc), trityl group (trityl), carbobenzoxy-(Cbz) (Cbz), trichloro-ethoxycarbonyl (Troc) or replace or unsubstituted aryl or heteroaryl; And
Under any situation that has a sequence ZAZ, having a member in this sequence at least must not be covalent linkage.
In some embodiment, work as R
6Be H, L is C=O, when Q does not exist, and R
7Not hydrogen, C
1-6Aryl alkyl or replacement or unsubstituted or heteroaryl.In some embodiment, work as R
6Be H, when Q does not exist, R
7Not at " protecting group in the organic synthesis " (Greene, T.W. and Wuts, P.G.M, JohnWiley ﹠amp; Sons, 1999) or the protecting group described in " protecting group " (Kocienski, P.J., Georg ThiemeVerlag, 1994).
In some embodiments, R
1, R
2, R
3And R
4Be selected from C
1-6Alkyl or C
1-6Aralkyl.In the preferred implementation, R
2And R
4Be C
1-6Alkyl, R
1And R
3Be C
1-6Alkyl.In the most preferred embodiment, R
2And R
4Be isobutyl-, R
1Be 2-styroyl, R
3Be phenmethyl.
In some embodiment, L and Q do not exist, R
7Be selected from C
1-6Alkyl, C
1-6Thiazolinyl, C
1-6Alkynyl, C
1-6Aralkyl and C
1-6Heteroaralkyl.In some this type of embodiment, R
6Be C
1-6Alkyl, R
7Be selected from butyl, allyl group, propargyl, phenmethyl, 2-pyridyl, 3-pyridyl and 4-pyridyl.
In the other embodiment, L is SO
2, Q does not exist, R
7Be selected from C
1-6Alkyl and aryl.In some this type of embodiment, R
7Be selected from methyl and phenyl.
In some embodiment, L is C=O, R
7Be selected from C
1-6Alkyl, C
1-6Thiazolinyl, C
1-6Alkynyl, aryl, C
1-6Aralkyl, heteroaryl, C
1-6Heteroaralkyl, R
8ZA-C
1-8Alkyl-, R
11Z-C
1-8Alkyl-, (R
8O) (R
9O) P (=O) O-C
1-8Alkyl-, (R
8O) (R
9O) P (=O) O-C
1-8Alkyl-ZAZ-C
1-8Alkyl-, (R
8O) (R
9O) P (=O) O-C
1-8Alkyl-Z-C
1-8Alkyl-, R
8ZA-C
1-8Alkyl-ZAZ-C
1-8Alkyl-, heterocyclic radical MZAZ-C
1-8Alkyl-, (R
10)
2N-C
1-8Alkyl-, (R
10)
3N
+-C
1-8Alkyl-, heterocyclic radical M-, carbocylic radical M-, R
11SO
2C
1-8Alkyl-and R
11SO
2NH-, wherein each existence of Z and A is independently, is not covalent linkage.In some embodiment, L is C=O, and Q does not exist, R
7Be H.
In some embodiment, R
6Be C
1-6Alkyl, R
7Be C
1-6Alkyl, Q does not exist, and L is C=O.In some this type of embodiment, R
7Be ethyl, sec.-propyl, 2,2,2-trifluoroethyl or 2-(methylsulfonyl) ethyl.
In the other embodiment, L is C=O, and Q does not exist, R
7Be C
1-6Alkyl.In some this type of embodiment, R
7Be selected from 2-styroyl, phenmethyl, (4-methoxyphenyl) methyl, (4-chloro-phenyl-) methyl and (4-fluorophenyl) methyl.
In the other embodiment, L is C=O, and Q does not exist, R
6Be C
1-6Alkyl, R
7Be aryl.In some this type of embodiment, R
7Be that replace or unsubstituted phenyl.
In some embodiment, L is C=O, and Q does not exist or is O, and n is 0 or 1, R
7For-(CH
2)
nCarbocylic radical.In some this type of embodiment, R
7Be cyclopropyl or cyclohexyl.
In some embodiment, L and A are C=O, and Q does not exist, and Z is O, and n is the integer (being preferably 1) of 1-8, R
7Be selected from R
8ZA-C
1-8Alkyl-, R
11Z-C
1-8Alkyl-, R
8ZA-C
1- 8Alkyl-ZAZ-C
1-8Alkyl-, (R
8O) (R
9O) P (=O) O-C
1-8Alkyl-ZAZ-C
1-8Alkyl-, (R
8O) (R
9O) P (=O) O-C
1-8Alkyl-Z-C
1-8Alkyl-and heterocyclic radical MZAZ-C
1-8Alkyl-, wherein each existence of A is independently, is not covalent linkage.In some this type of embodiment, R
7Be heterocyclic radical MZAZ-C
1-8Alkyl-, wherein heterocyclic radical for replace or unsubstituted oxo dioxa cyclopentenyl or N (R
12) (R
13), R wherein
12And R
13Common is C
1-6Alkyl-Y-C
1-6Alkyl (is preferably C
1-3Alkyl-Y-C
1-3Alkyl), form ring thus.
Some preferred embodiment in, L is C=O, Q does not exist, n is the integer of 1-8, R
7Be selected from (R
8O) (R
9O) P (=O) O-C
1-8Alkyl-, (R
10)
2NC
1-8Alkyl, (R
10)
3N
+(CH
2)
n-and heterocyclic radical-M-.In some this type of embodiment, R
7For-C
1-8Alkyl N (R
10)
2Or-C
1-8Alkyl N
+(R
10)
3, R wherein
10Be C
1-6Alkyl.In some other this type of embodiment, R
7Be heterocyclic radical M-, wherein heterocyclic radical is selected from morpholino, piperidino-(1-position only), Piperazino, pyrrolidino.
In some embodiment, L is C=O, R
6Be C
1-6Alkyl, Q are selected from O and NH, R
7Be selected from C
1-6Alkyl, heterocyclic radical-M, C
1-6Aralkyl and C
1-6Heteroaralkyl.In other the embodiment, L is C=O, R
6Be C
1-6Alkyl, Q are selected from O and NH, R
7Be C
1-6Alkyl, wherein C
1-6Alkyl is selected from methyl, ethyl and sec.-propyl.In the other embodiment, L is C=O, R
6Be C
1-6Alkyl, Q are selected from O and NH, R
7Be C
1-6Aralkyl, wherein aralkyl is a phenmethyl.In other embodiments, L is C=O, R
6Be C
1-6Alkyl, Q are selected from O and NH, R
7Be C
1-6Heteroaralkyl, wherein heteroaralkyl is (4-pyridyl) methyl.
In some embodiment, L does not exist or is C=O, R
6And R
7Common is C
1-6Alkyl-Y-C
1-6Alkyl, C
1-6Alkyl-ZA-C
1-6Alkyl or C
1-6Alkyl-A, wherein to deposit be independently to each of Z and A, is not covalent linkage, forms ring thus.In some preferred implementation, L is C=O, and Q and Y do not exist, R
6And R
7Common is C
1-3Alkyl-Y-C
1-3Alkyl.In another preferred implementation, L and Q do not exist, R
6And R
7Common is C
1-3Alkyl-Y-C
1-3Alkyl.In another preferred implementation, L is C=O, and Q does not exist, and Y is selected from NH and C
1-6Alkyl, R
6And R
7Common is C
1-3Alkyl-Y-C
1-3Alkyl.In another preferred implementation, L is C=O, and Y does not exist, R
6And R
7Common is C
1-3Alkyl-Y-C
1-3Alkyl.In another preferred implementation, L and A are C=O, R
6And R
7Common is C
1-2Alkyl-ZA-C
1-2Alkyl.In another preferred implementation, L and A are C=O, R
6And R
7Common is C
2-3Alkyl-A.
In some embodiment, the compound of formula I has following stereochemistry:
In the preferred implementation, inhibitor has structure or its pharmacy acceptable salt of formula II,
Wherein each A independently is selected from C=O, C=S and SO
2Preferred C=O or
When adjacent with the Z that exists, A is optional to be covalent linkage;
L does not exist or is selected from C=O, C=S and SO
2, preferred L does not exist or is C=O;
M does not exist or is C
1-12Alkyl is preferably C
1-8Alkyl;
Q does not exist or is selected from O, NH and N-C
1-6Alkyl, preferred Q do not exist or are O or NH,
Most preferably Q does not exist or is O;
X is selected from O, NH and N-C
1-6Alkyl is preferably O;
Y does not exist or is selected from O, NH and N-C
1-6Alkyl, S, SO, SO
2, CHOR
10And CHCO
2R
10
Each Z independently is selected from O, S, NH and N-C
1-6Alkyl is preferably O; Or
When adjacent with the A that exists, Z is optional to be covalent linkage;
R
2And R
4Independently be selected from C separately
1-6Alkyl, C
1-6Hydroxyalkyl, C
1-6Alkoxyalkyl, aryl and C
1-6Aralkyl, any group wherein randomly (are comprised C by one or more acid amides, amine, carboxylic acid (or its salt), ester
1-5Alkyl ester and aryl ester), mercaptan or thioether substituting group replace;
R
5Be N (R
6) LQR
7
R
6Be selected from hydrogen, OH and C
1-6Alkyl is preferably C
1-6Alkyl;
R
7Be selected from hydrogen, C
1-6Alkyl, C
1-6Thiazolinyl, C
1-6Alkynyl, aryl, C
1-6Aralkyl, heteroaryl, C
1-6Heteroaralkyl, R
8ZAZ-C
1-8Alkyl-, R
11Z-C
1-8Alkyl-, (R
8O) (R
9O) P (=O) O-C
1-8Alkyl-ZAZ-C
1-8Alkyl-, R
8ZAZ-C
1-8Alkyl-ZAZ-C
1-8Alkyl-, heterocyclic radical MZAZ-C
1-8Alkyl-, (R
8O) (R
9O) P (=O) O-C
1-8Alkyl-, (R
10)
2N-C
1-12Alkyl-, (R
10)
3N
+-C
1-12Alkyl-, heterocyclic radical M-, carbocylic radical M-, R
11SO
2C
1-8Alkyl-and R
11SO
2NH is preferably selected from C
1-6Alkyl, C
1-6Thiazolinyl, C
1-6Alkynyl, aryl, C
1-6Aralkyl, heteroaryl, C
1-6Heteroaralkyl, R
8ZA-C
1-8Alkyl-, R
11Z-C
1-8Alkyl-, (R
8O) (R
9O) P (=O) O-C
1-8Alkyl-ZAZ-C
1-8Alkyl-, (R
8O) (R
9O) P (=O) O-C
1-8Alkyl-Z-C
1-8Alkyl-, R
8ZA-C
1-8Alkyl-ZAZ-C
1-8Alkyl-, heterocyclic radical MZAZ-C
1-8Alkyl-, (R
8O) (R
9O) P (=O) O-C
1-8Alkyl-, (R
10)
2N-C
1-8Alkyl-, (R
10)
3N
+-C
1-8Alkyl-, heterocyclic radical M-, carbocylic radical M-, R
11SO
2C
1-8Alkyl-and R
11SO
2NH, wherein each existence of Z and A is independently, is not covalent linkage; Or
R
6And R
7Common is C
1-6Alkyl-Y-C
1-6Alkyl, C
1-6Alkyl-ZAZ-C
1-6Alkyl, ZAZ-C
1-6Alkyl-ZAZ-C
1-6Alkyl, ZAZ-C
1-6Alkyl-ZAZ or C
1-6Alkyl-A forms ring thus; Be preferably C
1-2Alkyl-Y-C
1-2Alkyl, C
1-2Alkyl-ZA-C
1-2Alkyl, A-C
1-2Alkyl-ZA-C
1-2Alkyl, A-C
1-3Alkyl-A or C
1-4Alkyl-A, wherein each existence of Z and A is independently, is not covalent linkage;
R
8And R
9Independently be selected from hydrogen, metallic cation, C
1-6Alkyl, C
1-6Thiazolinyl, C
1-6Alkynyl, aryl, heteroaryl, C
1-6Aralkyl and C
1-6Heteroaralkyl is preferably selected from hydrogen, metallic cation, C
1-6Alkyl, or R
8And R
9Common is C
1-6Alkyl forms ring thus;
Each R
10Independently be selected from hydrogen and C
1-6Alkyl is preferably C
1-6Alkyl; And
R
11Independently be selected from hydrogen, C
1-6Alkyl, C
1-6Thiazolinyl, C
1-6Alkynyl, carbocylic radical, heterocyclic radical, aryl, heteroaryl, C
1-6Aralkyl and C
1-6Heteroaralkyl, condition are to work as R
6Be H or CH
3, and Q is not when existing, LR
7Not hydrogen, unsubstituted C
1-6Alkyl C=O, amino acid whose another chain, tertbutyloxycarbonyl (Boc), benzoyl (Bz), fluorenes-9-base methoxycarbonyl (Fmoc), trityl group (trityl), carbobenzoxy-(Cbz) (Cbz), trichloro-ethoxycarbonyl (Troc) or replace or unsubstituted aryl or heteroaryl; And
Under any situation that has a sequence ZAZ, having a member in this sequence at least must not be covalent linkage.
In some embodiment, L is C=O, and Q does not exist, and X is O, R
6Be H, R
2And R
4Be selected from C
1-6Alkyl and C
1-6Aralkyl.In preferred this type of embodiment, R
2And R
4Be C
1-6Alkyl.In most preferred this type of embodiment, R
2And R
4Be isobutyl-.
In some embodiment, L is C=O, and Q does not exist, and X is O, R
6Be H, R
2And R
4Be isobutyl-, R
7Be heterocyclic radical M-, wherein heterocyclic radical is nitrogenous assorted base, as Piperazino (comprising N-(low alkyl group) Piperazino), morpholino and piperidino-(1-position only).In preferred this type of embodiment, M is CH
2
In some embodiment, the compound of formula II is selected from
In some embodiment, motif compound is that sequence number is the phosphatic prodrug of 09/569748 the disclosed compound of U. S. application (its whole content being carried out comprehensive reference here).Be used to suppress structure or its pharmacy acceptable salt that the active inhibitor prodrugs of chymotrypsin-like (CT-L) of Ntn has formula (III)
Wherein X is selected from O, NH and N-alkyl, is preferably O;
R
1, R
2, R
3And R
4Independently be selected from the group of hydrogen and formula IV, restricted condition is R
1, R
2, R
3And R
4In at least one is the group of formula IV;
R
5, R
6, R
7And R
8Independently be selected from C
1-6Alkyl, C
1-6Hydroxyalkyl, C
1-6Alkoxyalkyl, aryl and C
1-6Aralkyl, any group wherein randomly be selected from acid amides, amine, carboxylic acid or its pharmacy acceptable salt, carboxylicesters, mercaptan or thioether in group replace;
R
9Be amino acid whose another chain, hydrogen, C
1-6Acyl group, protecting group, aryl or heteroaryl, wherein substituting group can comprise halogen, carbonyl, nitro, hydroxyl, aryl and C
1-5Alkyl;
R
10And R
11Independently be selected from hydrogen and C
1-6Alkyl, or R
10And R
11Common carbocyclic ring or the heterocycle that forms 3-6 unit;
R
12And R
13Independently be selected from hydrogen, metallic cation, C
1-6Alkyl and C
1-6Aralkyl, or R
12And R
13Common expression C
1-6Alkyl forms ring thus; And
L does not exist or is selected from-CO
2Or-C (=S) O.
The synthetic field of peptide known suitable N end protecting group comprises tertbutyloxycarbonyl (Boc), benzoyl (Bz), fluorenes-9-base methoxycarbonyl (Fmoc), trityl group (trityl) and trichloro-ethoxycarbonyl (Troc) etc.Carbobenzoxy-(Cbz) or tertbutyloxycarbonyl various N protecting groups such as (Boc) that the synthetic field of peptide is known; Dicyclohexylcarbodiimide (DCC), 1,3-DIC (DIC), 1-(3-dimethylamino-propyl)-3-ethyl carbodiimide (EDC), N-hydroxyl azepine benzotriazole (HATU), the use of carbonyl dimidazoles or I-hydroxybenzotriazole one water thing various coupling reagent such as (HOBT), and various cutting conditions: for example, trifluoroacetic acid (TFA), contain two of HCl
Alkane in organic solvent (as methyl alcohol or ethyl acetate), carries out hydrogenation under the Pd-C catalysis, three (trifluoroacetic acid) boron and cyanogen bromides, and in solution, react, segregation and purify intermediates are equally applicable to the preparation of motif compound.
In some embodiments, R
1, R
2, R
3And R
4In any two be hydrogen, R
1, R
2, R
3And R
4In any two structures with formula IV.In the preferred implementation, R
1, R
2, R
3And R
4In any three be hydrogen, R
1, R
2, R
3And R
4In any one have the structure of formula IV.In the most preferred embodiment, R
1Structure with formula IV, R
2, R
3And R
4Be hydrogen.
In some embodiment, R
5, R
6, R
7And R
8Be C
1-6Alkyl or C
1-6Aralkyl.Preferred embodiment, R
6And R
8Be C
1-6Alkyl, R
5And R
7Be C
1-6Aralkyl.In the most preferred embodiment, R
6And R
8Be isobutyl-, R
5Be 2-styroyl, R
7Be phenmethyl.In some embodiment, R
9Be selected from hydrogen, C
1-6Acyl group or protecting group.Preferred embodiment, R
9Be hydrogen or ethanoyl.In the most preferred embodiment, R
9Be ethanoyl.
In some embodiment, R
10And R
11Be selected from hydrogen and C
1-6Alkyl.One preferred embodiment in, R
10Be hydrogen, R
11Be C
1-6Alkyl.Another preferred embodiment in, R
10Be hydrogen, R
11Be methyl.Another preferred embodiment in, R
10And R
11Be hydrogen.In some embodiment, R
12And R
13Be C
1-6Alkyl, metallic cation or C
1-6Aralkyl.Some preferred embodiment in, R
12And R
13Be selected from benzyl, the tertiary butyl and sodium cation.In the preferred embodiment, R
12And R
13Be the benzyl or the tertiary butyl.In the most preferred embodiment, R
12And R
13In at least one is a sodium cation.
Some embodiment, the compound of formula III has following stereochemistry:
Preferred embodiment, inhibitor has structure or its pharmacy acceptable salt of formula V,
Wherein, X is selected from O, NH or N-alkyl, is preferably O;
R
1, R
2, R
3And R
4Independently be selected from the group of hydrogen and formula IV, restricted condition is R
1, R
2, R
3And R
4In at least one is the group of formula IV;
R
6And R
8Independently be selected from C
1-6Alkyl, C
1-6Hydroxyalkyl, C
1-6 alkaneOxygen base alkyl, aryl and C
1-6The group that aralkyl, any group wherein randomly are selected from acid amides, amine, carboxylic acid or its pharmacy acceptable salt, carboxylicesters, mercaptan and thioether replaces;
R
9Be amino acid whose another chain, hydrogen, acyl group, protecting group, aryl or heteroaryl, wherein substituting group can comprise halogen, carbonyl, nitro, hydroxyl, aryl and C
1-5Alkyl.The synthetic field of peptide known suitable N end protecting group comprises tertbutyloxycarbonyl (Boc), benzoyl (Bz), fluorenes-9-base methoxycarbonyl (Fmoc), trityl group (trityl) and trichloro-ethoxycarbonyl (Troc) etc.; And
In some embodiments, R
1, R
2, R
3And R
4In any two be hydrogen, R
1, R
2, R
3And R
4In any two structures with formula IV.Preferred embodiment, R
1, R
2, R
3And R
4In any three be hydrogen, R
1, R
2, R
3And R
4In any one have the structure of formula IV.In the most preferred embodiment, R
1Structure with formula IV, R
2, R
3And R
4Be hydrogen.
In some embodiment, R
6And R
8Be C
1-6Alkyl or C
1-6Aralkyl.Preferred embodiment, R
6And R
8Be C
1-6Alkyl.In the most preferred embodiment, R
6And R
8Be isobutyl-.In some embodiment, R
9Be selected from hydrogen, C
1-6Acyl group or protecting group.Preferred embodiment, R
9Be hydrogen or ethanoyl.In the most preferred embodiment, R
9Be ethanoyl.
In some embodiment, R
10And R
11Be selected from hydrogen and C
1-6Alkyl.One preferred embodiment in, R
10Be hydrogen, R
11Be C
1-6Alkyl.Another preferred embodiment in, R
10Be hydrogen, R
11Be methyl.Another preferred embodiment in, R
10And R
11Be hydrogen.In some embodiment, R
12And R
13Be C
1-6Alkyl, metallic cation or C
1-6Aralkyl.Some preferred embodiment in, R
12And R
13Be selected from benzyl, the tertiary butyl and sodium cation.In the preferred embodiment, R
12And R
13Be the benzyl and the tertiary butyl.In the most preferred embodiment, R
12And R
13In at least one is a sodium cation.
In some embodiment, R
6And R
8Be C
1-6Alkyl.Preferred embodiment, R
6And R
8Be isobutyl-.Preferred embodiment, R
9Be hydrogen or ethanoyl.In the most preferred embodiment, R
9Be ethanoyl.One preferred embodiment in, R
10Be hydrogen, R
11Be methyl.Another preferred embodiment in, R
10And R
11Be hydrogen.In some embodiment, R
12And R
13Be C
1-6Alkyl, metallic cation or C
1-6Aralkyl.Some preferred embodiment in, R
12And R
13Be selected from benzyl, the tertiary butyl and sodium cation.In the preferred embodiment, R
12And R
13Be the benzyl and the tertiary butyl.In the most preferred embodiment, R
12And R
13In at least one is a sodium cation.
In some embodiment, get rid of US6 especially, disclosed compound, the whole content of this patent disclosure of comprehensive reference here in 831,099.
One aspect of the present invention relates to a kind of medicine equipment that comprises composition disclosed herein, and said composition comprises the inhibitor with structure any among formula I, II, III or the V.In a kind of embodiment, be combined with said composition in medicine equipment inside.In some embodiment, this medicine equipment is the gel that contains polymeric matrix or ceramic substrate and inhibitor.Described polymkeric substance can be naturally occurring or synthetic.In the another kind of embodiment, described gel is as drug depot, tackiness agent, suture, barrier or sealing agent.
Another aspect of the present invention relates to a kind of medicine equipment that comprises matrix, is equipped with the inhibitor of structure any among formula I, II, III or the V on a surface of this matrix.In a kind of embodiment, this inhibitor directly places on the medicine equipment.In the another kind of embodiment, the coating that is covered on the medicine equipment contains polymeric matrix or ceramic substrate in this coating, wherein dispersed or dissolved the inhibitor of structure any among formula I disclosed herein, II, III or the V.
In a kind of embodiment, this medicine equipment be crown (tube chamber) support, intravascular stent, periphery (tube chamber) support or biliary tract prosthesis.More specifically, support of the present invention is a kind of expandable stent.When comprising the matrix with inhibitor of any structure among formula I, II, III or the V and apply, this matrix is flexible, with compression and the expansion state of complying with this expandable stent.The another embodiment of the invention kind, this support have at least a part can insert or the body of implant patient in, wherein this part has a surface to be fit to contact with body tissue, wherein this surface has at least a part to apply the inhibitor with any structure among formula I, II, III or the V, or contain the coating of matrix, the inhibitor that wherein dissolves or disperseed to have any structure among formula I, II, III or the V.United States Patent (USP) 4,733,665 disclose a kind of example of suitable holder, and this patent is reference in addition as a whole here.
In the another kind of embodiment, medicine equipment of the present invention is a kind of surgical instruments, as apparatus, surgery encapsulant or vessel supporter (vascular support) in blood vessel implant, the tube chamber.More specifically, medicine equipment of the present invention is a conduit, implanted blood vessel transfusion port (implantable vasularaccess port), central venous catheter, ductus arteriosus, the artificial blood vessel, intraaortic balloon pump, suture, heart chamber auxiliary pump, medicament elution barrier (drug-eluting barrier), binding agent, the blood vessel coating, blood vessel is outer/blood vessel around supporting apparatus (extra/perivascular support), blood filter or the strainer that is suitable in blood vessel, using, these apparatuses are directly with having formula I, II, the inhibitor of any structure applies among III or the V, or has formula I with comprising, II, the matrix of the inhibitor of any structure applies among III or the V.
In some embodiment, the inhibitor of intraluminal medical device any structure in having formula I, II, III or V applies or applies through the coating with inhibitor of any structure among formula I, II, III or the V that contains biological tolerance matrix and be scattered in the polymkeric substance, described apparatus has an internal surface and an outside surface, in internal surface or outside surface or both, have at least a part coated.
In some embodiment, medicine equipment can be used for preventing postangioplasty restenosis.This medicine instrument also can have the inhibitor of any structure among formula I, II, III or the V by topical administration, is used for the treatment of various diseases and illness.Such disease comprises relevant damage and virus infection and the propagation of tissue injury, hyperplasia phlegm disease, severe psoriatic or psoriasis arthropathica, muscular dystrophy, chronic infectious disease, immunoreaction abnormity, the illness that relates to vulnerable plaque, ischemic conditions that restenosis, inflammation, rheumatoid arthritis, inflammation cause with illness.Phlegm disease and examples of disorders with the medical device treatment that comprises pharmaceutical pack quilt of the present invention comprise that atherosclerosis, acute coronary artery syndrome, alzheimer ' Mo Ershi disease, cancer, heating, muscle give up with (atrophy), denervation, angiemphraxis, apoplexy, HIV infection, nerve injury, follow acidosic renal failure and liver failure (for example to see Goldberg, United States Patent (USP) 5,340,736.)
Term " C
X-yAlkyl " refer to saturated hydrocarbyl that replace or unsubstituted, comprise the straight chained alkyl and the branched-chain alkyl that contain x-y carbon in the chain; Comprise trifluoromethyl and 2,2, haloalkyls such as 2-trifluoroethyl; If C
0Represent hydrogen when alkyl is positioned at terminal position, when being positioned at chain inside, represent a key as if this group.Term " C
2-yThiazolinyl " and " C
2-yAlkynyl " refer to unsaturated aliphatic base that replace or unsubstituted, similar with abovementioned alkyl aspect length and contingent replacement, but contain at least one two keys or triple bond respectively.
Term " alkoxyl group " refers to have an alkyl of bonded oxygen with it.Representational alkoxyl group comprises methoxyl group, oxyethyl group, propoxy-, tert.-butoxy etc." ether " is by two alkyl that oxygen is covalently bound.Therefore, to make alkyl become the substituting group of this alkyl of ether be alkoxyl group or be similar to alkoxyl group.
Term " C
1-6Alkoxyalkyl " refer to the C that alkoxy replaces
1-6Alkyl forms ether thus.
Term " C used herein
1-6Aralkyl " refer to the C that replaced by aryl
1-6Alkyl.
Term " amine " and " amino " approved by this area, refers to amine and salt thereof unsubstituted and that replace, for example the part that can represent with following general formula:
R wherein
9, R
10And R
10' independent separately expression hydrogen, alkyl, thiazolinyl ,-(CH
2)
m-R
8Or R
9And R
10Together with it
Nitrogen-atoms form the heterocycle that has 4-8 atom in the ring structure together; R
8Expression aryl, cycloalkyl, cycloalkenyl group, heterocyclic radical or many cyclic groups; M is 0 or the integer of 1-8.Preferred embodiment, R
9Or R
10In have only one for carbonyl, for example, R
9, R
10Can not form imide jointly with nitrogen.In the preferred embodiment, R
9And R
10(optional R
10') independent separately expression hydrogen, alkyl, thiazolinyl or-(CH
2)
m-R
8In some embodiment, amino is alkalescence, means its pK
a〉=7.00.The pK of the protonated form of these functional groups
aBe more than 7.00.
Term " acid amides " and " amido " are the amino carbonyl that replaces by this area approval, comprise the part that can represent with general formula:
R wherein
9And R
10With aforementioned definition.The optimal way of acid amides will not comprise the imide of potentially unstable.
Term used herein " aryl " comprises replacement or unsubstituted 5 yuan, 6 yuan and 7 yuan of monocyclic aromatic bases, and wherein each atom in the ring is carbon.Term " aryl " also comprises the polycyclic system with two or more rings, wherein, two in abutting connection with shared two or more carbon of ring (wherein at least one ring for aromatic nucleus), and other ring can be for example cycloalkyl, cycloalkenyl group, cycloalkynyl radical, aryl, heteroaryl and/or heterocyclic radical.Aryl comprises benzene, naphthalene, phenanthrene, phenol, aniline.
Term used herein " carbocyclic ring " and " carbocylic radical " refer to replace or unsubstituted non-aromatic ring, and wherein each atom in the ring is carbon.Term " carbocyclic ring " and " carbocylic radical " also comprise the polycyclic system with two or more rings, wherein, two in abutting connection with shared two or more carbon of ring (wherein at least one ring for carbocyclic ring), and other ring can be for example cycloalkyl, cycloalkenyl group, cycloalkynyl radical, aryl, heteroaryl and/or heterocyclic radical.
Term " carbonyl " approved by this area, comprises the part that can represent with following general formula:
Wherein X is a key or expression oxygen or sulphur, R
11Expression hydrogen, alkyl, thiazolinyl ,-(CH
2)
m-R
8Or pharmacy acceptable salt, R
11' expression hydrogen, alkyl, thiazolinyl or-(CH
2)
m-R
8, wherein m and R
8With aforementioned definition.When X is an oxygen, and R
11Or R
11' when being not hydrogen, this structural formula is represented " ester ".When X is oxygen and R
11During for hydrogen, this structural formula is represented " carboxylic acid ".
" enzyme " used herein can be any imperfect protein molecule or the whole protein molecule of finishing chemical reaction with catalytic way.Such enzyme can be natural enzyme, merge enzyme, the mutant enzyme of proenzyme, apoenzyme, anaenzyme, farnesylation enzyme, ubiquitin enzyme, fat acylase, Mang ox geranyl enzyme (gerangeranylated enzyme), GPI ligase enzyme, fat ligase enzyme, prenyl enzyme, naturally occurring or artificial preparation, have side chain or backbone modifications enzyme, have leader sequence enzyme, with non-proteic substance compound enzyme (as proteoglycan, proteoliposome).Available any method prepares enzyme, comprises nature expression, promotion expression, clone, various based on solution and synthetic based on the solid peptide, and the known similar approach of those skilled in the art.
Term " C used herein
1-6Heteroaralkyl " refer to the C that replaced by heteroaryl
1-6Alkyl.
Term " heteroaryl " comprises the first aromatic ring structure of 5-7 replacement or unsubstituted, and more preferably 5-6 unit encircles, and its ring structure comprises 1-4 heteroatoms.Term " heteroaryl " also comprises the polycyclic system with two or more rings, wherein, two in abutting connection with shared two or more carbon of ring (wherein at least one ring for hetero-aromatic ring), and other ring can be for example cycloalkyl, cycloalkenyl group, cycloalkynyl radical, aryl, heteroaryl and/or heterocyclic radical.Heteroaryl comprises, for example, pyrroles, furans, thiophene, imidazoles,
Azoles, thiazole, triazole, pyrazoles, pyridine, pyrazine, pyridazine and pyrimidine etc.
Term used herein " heteroatoms " refers to any atoms of elements beyond carbon or the hydrogen.Preferred heteroatoms is nitrogen, oxygen, p and s.
" " refer to the first non-aromatic ring structure of 3-10 that replace or unsubstituted, more preferably 3-7 unit encircles heterocyclic radical term, and its ring structure comprises 1-4 heteroatoms.Term " heterocyclic radical " also comprises the polycyclic system with two or more rings, wherein, two in abutting connection with shared two or more carbon of ring (wherein at least one ring for heterocycle), and other ring can be for example cycloalkyl, cycloalkenyl group, cycloalkynyl radical, aryl, heteroaryl and/or heterocyclic radical.Heterocyclic radical comprises, for example, and piperidines, piperazine, tetramethyleneimine, morpholine, lactone, lactan etc.
Term " C
1-6Hydroxyalkyl " refers to the C that replaced by hydroxyl
1-6Alkyl.
Term used herein " inhibitor " refer to block or the compound that reduces enzymic activity (for example, inhibition suppresses the various catalytic activitys of 20S proteasome to the proteolytic cleavage such as the fluorescence peptide substrates of standards such as suc-LLVY-AMC, Box-LLR-AMC and Z-LLE-AMC).The inhibition of being at war with property of inhibitor, uncompetitive suppress or noncompetitive suppresses.Inhibitor can carry out reversible or irreversible fixation, so this term comprises the compound as the suicide substrate of enzyme.Inhibitor can be modified near one or more position on the reactive site of enzyme or it, and perhaps it causes conformational change in the other places of enzyme.
" peptide " comprises that not only the standard amide with standard alpha-substitution base connects, also uses the peptide mimics that is hereinafter described in detail, other modification connection, side chain and the side chain that non-natural exists to modify usually term used herein.
Term " many cyclic groups " or " polycyclic " refer to two or more rings (for example, cycloalkyl, cycloalkenyl group, cycloalkynyl radical, aryl, heteroaryl and/or heterocyclic radical), wherein two adjacency are encircled shared two or more carbon, and for example, these rings are " condensed ring ".Each ring in many rings can be that replace or unsubstituted.
Term " prevention " is approved by this area, when being used for the part and sending out syndromess such as diseases such as illnesss such as (as pain), cancer, heart failure or any other medical conditions again, for known in the art, comprise individuality is used composition, make than the individuality of not accepting composition, reduced it and the symptom frequency of medical conditions occurred or postpone the illness outbreak.Therefore, the prevention of cancer comprises, for example, be subjected in the patient population of prophylactic treatment, for example on statistics level and/or clinical conspicuous level, with respect to the control population for the treatment of, reduced the number that can detect cancer growth and/or, postponed to occur detectable cancer growth with respect to the control population for the treatment of.The prevention of transmissible disease comprises, for example, is subjected in the colony of prophylactic treatment, with respect to the control population for the treatment of, has reduced infectious diagnosis number, and/or with respect to the control population for the treatment of, has postponed to infect the outbreak of symptom.The prevention of pain comprises, for example, is subjected in the colony of prophylactic treatment, and with respect to the control population for the treatment of, the individual pain sensation alleviates or postpones appearance.
Term " prodrug " is included in the compound that changes into the therapeutic activity agent under the physiological condition.The common method of preparation prodrug comprises that being chosen in physiological condition issues the component that unboiled water is separated, to appear needed molecule.In other embodiment, by the enzymic activity conversion prodrug of host animal.
Term " preventative or therapeutic treatment " is approved by this area, comprises giving the host one or more kind test composition.If going out harmful illness (for example harmful situation of other of disease or host animal) in clinical manifestation gives before, so this treatment be preventative (promptly, it prevents that harmful situation of host is developed), if and after clinical manifestation goes out to be harmful to illness, give, so this treatment be curative (that is, it be intended to make the harmful situation that is occurred its side effect is alleviated, is improved or stable).
Term used herein " proteasome " comprises immunity protease body and structural protein enzyme body.
Term " replacement " refers to have the substituent part that replaces the hydrogen on one or more carbon in the main chain.Should understand, replace " or " quilt ... replace that " the implicit limitations condition that comprises is that this replacement should be basis with the valency that substituted atom and substituting group allowed, and should replace and generate stable compound (as can not spontaneous experience resetting conversion, cyclisation conversion, eliminate conversion etc.).Term used herein " replace " expectation comprises the organic compound substituting group of all permissions.Broadly, the substituting group of permission comprises acyclic and cyclic, ramose and unbranched, isocyclic and heterocyclic, fragrance and organic compound substituting group non-fragrance.The substituting group that allows can be one or more, and is identical or different with needed organic compound.For the present invention, heteroatomss such as nitrogen can have hydrogen substituting group and/or the organic compound substituting group that meets the valent any permission of heteroatoms described here.Substituting group can comprise; for example, halogen, hydroxyl, carbonyl (for example carboxyl, carbalkoxy, formyl radical or acyl group), thiocarbonyl (for example thioesters, thioacetic acid root close or the bamic acid root), alkoxyl group, phosphoryl, phosphate radical, phosphonate radical, phosphonous acid root, amino, amide group, amidine, imines, cyano group, nitro, azido-, sulfydryl, alkylthio, sulfate radical, sulfonate radical, sulphonamide, sulfahydantoin, alkylsulfonyl, heterocyclic radical, aralkyl or fragrance or fragrant assorted base section.The one skilled in the art should be understood that if desired itself can be substituted the substituting group on the hydrocarbon chain.
For tested methods of treatment, " the treatment significant quantity " of compound refers to the compound amount in the preparation, it is in the part as the dosage regimen that requires, to mammals (preferred people) when using, can accept standard clinically according to the imbalance that is used to treat or illness or cosmetic use,, realize mitigation symptoms, improve illness or delay seizure of disease applicable to the rational interests/risk ratio of any therapeutic treatment with for example.
" thioether " refers to have the alkyl as defined above of the sulphur part that is attached thereto to term.Preferred embodiment, thioether " represent with-S-alkyl.Representational sulfide group comprises methylthio group, ethylmercapto group etc.
" treatment " comprises to improve or to stablize the mode of individual illness, reverses, alleviates or stop symptom, clinical manifestation and the basic pathology (underlying pathology) of illness term used herein.
Selectivity to the 20S proteasome
Why useful enzyme inhibitors analogue disclosed herein and prodrug be, and part is because they suppress the effect of 20S proteasome.In addition, different with other 20S proteasome inhibitor, with respect to other proteolytic enzyme, compound disclosed herein has the selectivity of height to the 20S proteasome.That is to say that with respect to other proteolytic enzyme such as kethepsin, Calpain, papoid, Quimotrase, trypsinase, three peptidyl pepsidase II, this compound shows selectivity to the 20S proteasome.Enzyme inhibitors to the selectivity of 20S proteasome is: the enzyme inhibitors that concentration is lower than about 50 μ M suppresses to be used as to the catalytic activity performance of 20S proteasome, and other catalytic activity of proteinase such as kethepsin, Calpain, papoid, Quimotrase, trypsinase, three peptidyl pepsidase II are not shown restraining effect.Preferred embodiment, concentration is lower than the catalytic activity demonstration restraining effect of the enzyme inhibitors of about 10 μ M to the 20S proteasome, but under this concentration, other catalytic activity of proteinase is not shown inhibition.In the preferred embodiment, concentration is lower than the catalytic activity demonstration inhibition of the enzyme inhibitors of about 1 μ M to the 20S proteasome, but under this concentration, other catalytic activity of proteinase is not shown inhibition.Sequence number be people such as 09/569748 U. S. application (embodiment 2) and Stein (Biochem. (1996), 35,3899-3908) dynamic analysis of enzyme is disclosed.
To the active selectivity of chymotrypsin-like
Why useful the embodiment of enzyme inhibitors analogue as described herein and preceding drug compound is, also because they can effectively and optionally suppress the chymotrypsin-like activity (comparing with the PGPH activity with trypsin-like is active) of 20S proteasome.The chymotrypsin-like activity characterization of 20S proteasome is at the position of the big hydrophobic residue of next-door neighbour, and peptide is cut.Particularly, the chymotrypsin-like activity of Ntn lytic enzyme can be by determining the cutting of standard substrate.The example of this substrate is known in the art.For example, can use leucyl leucyl valyl tyrosine derivative.Sequence number be people such as 09/569748 U. S. application (embodiment 2) and Stein (Biochem. (1996), 35,3899-3908) dynamic analysis of enzyme is disclosed.
The purposes of enzyme inhibitors
Proteasome suppresses biological results to be had multiple.On cell levels, handle cells with various proteasome inhibitors, reported that morphological change and accent that the gathering of many ubiquitin proteins, cell occur die.Proteasome suppresses also to be proposed as possible antineoplaston strategy.Epoxomicin at first screening during antineoplastic compound the certified fact confirmed that proteasome can be used as the target of anti-tumor chemotherapeutic.Therefore, these compounds can be used for treating cancer.The inhibition of proteasome also is accompanied by the activation of inhibition NF-κ B and the level of stable p53.Therefore, The compounds of this invention also can be used for suppressing the activation of NF-κ B, the p53 level in the stabilized cell culture.Because NF-κ B is the main conditioning agent of inflammation, it is to be used for the attractive target that anti-inflammatory treatment is intervened.Therefore, The compounds of this invention can be used for treatment and follows chronically inflamed illness, includes but not limited to COPD, psoriatic, bronchitis, pulmonary emphysema and cystic fibrosis.
Disclosure compound can be used for treating the illness by the direct mediation of proteolysis function of proteasome, as amyotrophy, or by the indirect illness that mediates of the protein of proteasomes such as NF-κ B processing.Proteasome participates in relating to quick cancellation and the translation post-treatment that cell is regulated the protein (as enzyme) of (as cell cycle, genetic transcription and pathways metabolism), cell-cell communication and immune response (as antigen presentation).Object lesson discussed below comprises adjusting albumen such as amyloid-beta and cyclin bletilla transcription factor NF-KB.
Another embodiment of the invention is the purposes of compound disclosed herein in treatment neurodegenerative disease and illness, such disease and illness include but not limited to apoplexy, neural ischemia injury, neurotrauma is (as impact brain injury (percussive brain damage), Spinal injury and nervous system injury), multiple sclerosis and other immune-mediated neuropathy are (as Green-barre syndrome and modification thereof, acute motor axonal neuropathy, acute inflammation demyelinating polyneuropathy and Fei Xier syndromes), the HIV/AIDs dementia, axonomy, diabetic neuropathy, Parkinson's disease, Heng Tingdunshi disease, multiple sclerosis, bacterial meningitis, the parasitic meningitis, fungal meningitis and viral meningitis, encephalitis, vascular dementia, multi-infarct dementia, dementia with Lewy body (Lewy body dementia), Pi Keshi disease single-candidate blade profile dementia, cortex mo(u)ld bottom half dementia (as Huntington Chorea or stein-leventhal syndrome), focal cortex atrophy syndromes (as the primary aphasia), metabolic/toxic dementia (lacking) as chronic hypothyroidism or B12, and infect the dementia (as syphilis or chronic meningitis) that causes.
Alzheimer ' Mo Ershi disease is characterized by and deposits amyloid-beta (β-AP) in the senile plaque and the cerebrovascular.β-AP is the peptide fragment derived from the 39-42 amino acids of amyloid protein precursor (APP).At least three kinds of APP abnormal shapes (695,751 and 770 amino acid) are known.The road montage in addition of mRNA produces special-shaped; Normal process exerts an influence to a part of β-AP sequence, thereby prevents the generation of β-AP.It is believed that the abnormal processing that proteasome carries out protein causes containing abundant β-AP in the alzheimer ' Mo Ershi brain.APP processive enzyme in the rat contains the ten kinds of different subunits (22kDa-32kDa) of having an appointment.The 25kDa subunit has N terminal sequence X-Gln-Asn-Pro-Met-X-Thr-Gly-Thr-Ser, it and the β-subunit identical (Kojima, S. etc., Fed.Eur.Biochem.Soc., (1992) 304:57-60) of human megalin body (macropain).The APP processive enzyme is to Gln
15-Lys
16Key cuts; In the presence of calcium ion, this enzyme is also to Met
1-Asp
1Key and Asp
1-Ala
2Key cuts to discharge the extracellular domain of β-AP.
Therefore, a kind of embodiment is a kind of method for the treatment of alzheimer ' Mo Ershi disease, comprises the compound disclosed herein that gives individual effective dose (as, pharmaceutical composition).This treatment comprises the process velocity that reduces β-AP, reduces the formation speed of β-AP patch, reduces the formation speed of β-AP, and the clinical symptom that alleviates alzheimer ' Mo Ershi disease.
Other embodiment of the present invention relates to emaciation and muscular dystrophy.Proteasome is degraded to a large amount of protein in ripening stage reticulocyte and the vegetative period inoblast.In the Regular Insulin and serum cell of forfeiture, the speed of proteolysis almost doubles.Inhibition to proteasome has reduced proteolysis, thereby has reduced the loss of mytolin and the nitrogenous load in kidney or the liver.Inhibitor of the present invention be used for the treatment of such as cancer, chronic infectious disease, heating, muscle useless with (atrophy) and denervation, nerve injury, fasting, follow illnesss such as acidosic renal failure, diabetes and liver failure.For example referring to, Goldberg, United States Patent (USP) 5,340,736.Therefore embodiments of the present invention comprise the method for following purposes: the degradation speed that reduces myoprotein in the cell; Reduce the degradation speed of intracellular protein; Reduce the proteic degradation speed of p53 in the cell; Suppress the relevant cancer growth of p53.In these methods each all comprises makes cell (body is interior or external, as the muscle of individuality) contact with the compound disclosed herein (as pharmaceutical composition) of significant quantity.
The another kind of protein of proteasome processing is NF-κ B (a member of Rel protein family).Transcription activating protein Rel family can be divided into two classes, and the first kind need be carried out proteolysis processing, comprise p50 (NF-κ B1,105kDa) and p52 (NF-κ B2,100kDa).Second class does not need to carry out proteolysis processing, comprises p65 (RelA, Rel (c-Rel) and RelB).The Rel family member can form homodimer and heterodimer; For example NF-κ B is the p50-p65 heterodimer.After I κ B and p105 generation phosphorylation and ubiquitinization, these two protein obtain degraded and processing respectively, produce active NF-κ B, are displaced to nucleus from tenuigenin.Can also process (Palombella etc., Cell (1994) 78:773-785) to the p105 of ubiquitinization with the proteasome of purifying.Active NF-κ B and other activating transcription factor (as HMGI (Y)) constitute stereospecificity enhanser complex body (stereospecific enhancer complex), induce the selective expression of specific gene.
NF-κ B regulatory gene relates to immunity and inflammatory reaction, and the mitotic division activity.For example, the genes encoding of light chain immunoglobulin kappa gene, IL-2 receptor alpha chain gene, I class major histocompatibility complex expression of gene and a large amount of cytokine (for example IL-2, IL-6, granulocyte colony-stimulating factor and IFN-β) needs NF-κ B (Palombella etc., Cell (1994) 78:773-785).Some embodiments of the present invention comprise the method that influences IL-2, MCH-I, IL-6, TNF α, TNF-β or any other aforementioned protein expression level, and each method comprises the compound disclosed herein that gives individual effective dose.The complex body that comprises p50 is acute inflammation and immunoreactive quick mesosome (Thanos, D. and Maniatis, T., Cell (1995) 80:529-532).
The NF-κ B E-that also participates in encoding selects albumen, P-to select the cell adhesion expression of gene (Collins, T., Lab Invest. (1993) 68:499-508) of albumen, ICAM and VCAM-1.One embodiment of the present invention are (for example to suppress cell adhesion, select albumen, P-to select the cell adhesion of albumen, ICAM or VCAM-1 mediation by E-) method, comprise the compound disclosed herein (or pharmaceutical composition) that makes cells contacting (or use individuality) significant quantity.
NF-κ B also combines with HIV-enhancers/promoters specificity.Than the Nef of mac239, in control protein kinase bonded zone, the amino acid that the HIV of pbj14 regulates albumen Nef has two place's differences.It is believed that protein kinase carries out the signal indication to the phosphorylation of I κ B, trigger I κ B degraded by Ubiquitin-Proteasome Pathway.I κ B is released in the nucleus after degraded, thereby strengthens transcribe (Cohen, J., Science, (1995) 267:960) of HIV.Two kinds of embodiments of the present invention are a kind of methods that suppress or reduce individual infected by HIV, and a kind of method that reduces the viral gene expression level, and each method comprises the compound disclosed herein that gives individual effective dose.
The excessive generation of lipopolysaccharides (LPS) inductive cytokines such as TNF α is considered to the important factor of septic shock correlated process.In addition, people it is generally acknowledged that the first step of LPS activating cells is LPS and combines with specific membrane receptor.It is conjugated protein that the α of 20S proteasome complex body and β subunit have been accredited as LPS, illustrates that LPS inductive signal transduction may be the critical treatment target (Qureshi, N. etc., J.Immun. (2003) 171:1515-1525) of a kind of treatment or prevention of sepsis.Therefore, in some embodiment, The compounds of this invention can be used for suppressing TNF α, to prevent and/or treat septic shock.
The intracellular protein enzymolysis has produced and has been used to present to the immune response of the lymphocytic little peptide of T-to induce I class MHC to mediate.Immunity system is to infective virus or the autogenous cell that carinogenicity transforms has taken place screen.A kind of embodiment is a kind of method that intracellular antigen is presented that suppresses, and comprises cell is contacted with compound described here.The compounds of this invention can be used for treating Ia illness, repel (graft versus host disease (GVH disease)) and autoimmune disease as allergy, asthma, organ-/ tissue, include but not limited to lupus, rheumatoid arthritis, psoriatic, multiple sclerosis and inflammatory bowel (as ulcerative colitis and Crohn disease).Like this, another embodiment is a kind of method that is used to suppress the immunity system (as suppressing transplant rejection, allergy and asthma) of individuality, comprises the compound disclosed herein of individuality being used significant quantity.
The method of all constituents of the another kind of embodiment antigen peptide that to be a kind of change produced by proteasome or other Ntn with many catalytic activitys.For example, if the PGPH activity of 20S proteasome is suppressed by selectivity, this proteasome will generate the different antigen peptide of a cover, and in the MHC of cell surface molecule, present, suppress or the antigen peptide when active generates and presents such as the chymotrypsin-like of selectivity arrestin enzyme body and be unlike in without any enzyme.
Some proteasome inhibitor has blocked ubiquitin NF-κ B degraded and processing in vitro and in vivo.Proteasome inhibitor has also blocked the degraded of I κ B-α and the activation of NF-κ B (Palombella, et al.Cell (1994) 78:773-785; And Traenckner, et al., EMBO J. (1994) 13:5433-5441).One embodiment of the present invention are methods of a kind of I of inhibition κ B-α degraded, comprise cell is contacted with compound described here.Another kind of embodiment is a kind of NF-κ B born of the same parents intensive amount that reduces in cell, muscle, organ and the individuality, comprises cell, muscle, organ and compound individual and described here are contacted.
Need other eukaryotic transcription factor of proteolysis processing to comprise general transcription factor TFIIA, hsv VP16 accessory protein (the host cell factor), virus induction type IFN regulatory factor-2 albumen and film mating type sterol regulatory element conjugated protein-1.
Other embodiment of the present invention is the method in eukaryotic cell cycle that influence depends on cyclin, comprises making cell contact (external or body interior) with compound disclosed herein.Cyclin relates to the protein of cell cycle control.Proteasome participates in the degraded of cyclin.The example of cyclin comprises mitotic cell cyclin, G1 cyclin and cell periodic protein B.The degraded of cyclin makes cell can break away from a cell cycle phase (if any the silk division) and enters another stage (as differentiation).Think that all cyclin and p34.sup.cdc2 protein kinase or associated kinase associate.Proteolysis target signal framing is in amino acid 42-RAALGNISEN-50 (degraded frame).Evidence suggests that during mitotic division, cyclin is converted into form or the activating cells cyclin specificity ligase enzyme (Ciechanover, A., Cell, (1994) 79:13-21) that is subject to the ubiquitin ligase infringement.The inhibition of proteasome is suppressed the degraded of cyclin, thereby suppressed the propagation (Kumatori etc., Proc, Natl .Acad.Sci.USA (1990) 87:7071-7075) of cell (for example, in the relevant cancer of cyclin).One embodiment of the present invention are a kind of methods that individuality is carried out proliferative disease (as cancer, psoriatic or restenosis) treatment, comprise the compound disclosed herein of individuality being used significant quantity.The present invention also comprises and a kind of individuality is carried out the method for the relevant inflammation treatment of cyclin, comprises the compound described here to individual administering therapeutic significant quantity.
Other embodiment is that influence depends on method suppression therapy that the cancer protein of proteasome regulates or the method that suppresses the cancer growth, and every kind of method comprises makes cells contacting (in the body, as in individual body, or external) compound disclosed herein.HPV-16 and HPV-18 deutero-E6 protein boost dependency ATP with conjugation and the degraded of p53 in crude product reticulocyte lysate that relies on ubiquitin.The thermo-labile E1 of mutant has been presented under the non-allowance temperature, and recessive oncogene p53 accumulates in clone.The level that improves p53 can cause to transfer dies.The example of the proto-protein of Ubiquitin System degraded comprises c-Mos, c-Fos and c-Jun.A kind of embodiment is the relevant method of dying of transferring of a kind of p53 of treatment, comprises the compound disclosed herein of using significant quantity to individuality.
In the another kind of embodiment, disclosure compound is used for the treatment of parasitic infection, the infection that causes as protozoan parasite.These parasitic proteasomes are considered to relate generally to cytodifferentiation and replication activity (Paugam etc., Trends Parasitol.2003,19 (2): 55-59).In addition, when entamoeba contacts with proteasome inhibitor, show that the forfeiture packing forms ability.In some such embodiment, disclosure compound is used for the treatment of the parasite of human infection that protozoan parasite causes, this protozoan parasite is selected from plasmodium (Plasmodium sps.) and (comprises the plasmodium falciparum (P.falciparum) that causes malaria phlegm, Plasmodium vivax (P.vivax), malariae (P.malariae) and Plasmodium ovale (P.ovale)), trypanosoma (Trypanosoma sps.) (comprising the trypanosoma bocagei (T.brucei) that causes chagasic schizotrypanum cruzi (T.cruzi) and cause African lethargy), leishmaniasis (Leishmania sps.) (comprises Amazon leishmania (L.amazonensis), Leishmania donovani (L.donovani), leishmania infantum (L.infantum), leishmania mexicana (L.mexicana) etc.), Pneumocystis carinii Pneumocystis carinii) (a kind of known protozoon that causes that pneumonia takes place for aids patient and other immunosuppression patient), toxoplasma gondii (Toxoplasma gondii), entamoeba histolytica worm (Entamoeba histolytica), invade entamoeba worm (Entamoeba invadens) and giardia lamblia (Giardia lamblia).In some embodiment, disclosure compound is used for the treatment of the animal and the animal parasite that are caused by the protozoan parasite that is selected from cicada Er Manshi plasmodium (Plasmodium hermani), Cryptosporidium (Cryptosporidium sps.), Echinococcus granulosus (Echinococcus granulosus), Eimeria tenella (Eimeria tenella), neural sarcocystis (Sarcocysfis neurona) and Neurospora crassa (Neurospora crassa) to be infected.WO98/10779 has described other compound as the proteasome inhibitor of treatment parasitosis, its whole content is carried out comprehensive reference here.
In some embodiment, disclosure compound carries out irreversible inhibition to the proteasome activity in the parasite.Show that this irreversible inhibition lures that the enzymic activity in red corpuscle and the white corpuscle irretrievably stops into.In some this type of embodiment, be exposed to regard to the parasitic treatment with regard to anti-, the very long transformation period of hemocyte can provide and prolong protection again.In some embodiment, about carrying out the chemoprophylaxis aspect to infecting future, the very long transformation period of hemocyte can provide and prolong protection.
Also report, in bone object official culture, stimulated the formation of bone with 20S proteasome bonded inhibitor.In addition, when giving the such inhibitor of mouse systemic administration, some proteasome inhibitor raising bone volume and bone forming speed (Garrett J.R. etc. more than 70%, J.Clin.Invest. (2003) 111:1771-1782), thereby show that uiquitin-protease enzyme body machine (ubiquitin-proteasome machinery) is regulated osteoblastic differentiation and bone forming.Therefore, disclosure compound can be used for treating and/or preventing bone loss relative diseases such as osteoporosis.
Osseous tissue is the good source with the factor that stimulates the osteocyte ability.Therefore, the ox bone tissue extract not only contains the structural protein of the structural integrity of being responsible for keeping bone, also contains the biological activity bone growth factor that can stimulate osteocyte propagation.The protein families that is called as Delicious peptide (BMPs) that in these factors, comprises nearest report.All these somatomedins exert an influence to the cell (comprising osteocyte) of other type, comprise Hardy, M.H. wait describe relevant between the growth period, Delicious peptide (BMPs) differentially expressed evidence (Trans Genet (1992) 8:55-61) in hair follicle.Harris, S.E. etc. have described the influence (BoneMiner Res (1994) 9:855-863) of TGF β to expression of Substance in BMP-2 and other osteocyte.Reaching propagation during the cell maturation after the phase, the expression (Hardy etc., (1992) are on seeing) of BMP-2 has also appearred in ripe follicle.Therefore, The compounds of this invention also can be used for the hair follicle stimulating growth.
At last, also as diagnostic reagent (for example, the diagnostic reagent that diagnostic kit or clinical labororatory use), the protein (for example enzyme, transcription factor) that Ntn lytic enzymes such as proteasome are processed screens disclosure compound.Disclosure compound also as specificity in conjunction with X/MB1 subunit or α chain and the research reagent that suppresses associated proteolytic activity.For example, can determine the activity (and specific inhibitor) of other subunit of proteasome.
In maturation or reactivation process, most cells albumen is processed by proteolysis.Enzyme inhibitors disclosed herein can be used for determining whether cell, that grow or physiological process or output are subjected to the adjusting of the proteolytic activity of specific Ntn lytic enzyme.A kind of such method comprises: obtain organism, complete cellular preparations or cell extract; This organism, cellular preparations or cell extract are contacted with compound disclosed herein; Make organism, cellular preparations or the cell extract of contact compound contact monitor procedure or output with bashertron.The highly selective of compound disclosed herein can be eliminated or hint Ntn (for example, 20S proteasome) in given cell, that grow or physiological process rapidly and exactly.
Administration
Here describe the compound of preparation and can use by various forms the illness for the treatment of that its form depends on and patient's age, situation and body weight (as known in the art).For example, when carrying out oral administration of compound, it can be mixed with tablet, capsule, granule, pulvis or syrup; When perhaps carrying out the gi tract external administration, it can be mixed with injection (intravenous, intramuscular or subcutaneous), instillation preparation or suppository.During by the administration of eye mucosa path, it can be mixed with eye drops or Eye ointments.Can prepare these formulations by ordinary method, if desired, can be with the additive or the mixed with excipients of activeconstituents and any routine, as tackiness agent, disintegrating agent, lubricant, correctives, stablizer, suspending agent, emulsifying agent, coating material, cyclodextrin and/or buffer reagent.Though dosage changes along with symptom, patient's age and body weight, the character of illness that needs treatment or prevention and seriousness, administration path and pharmaceutical dosage form, usually, adult patient's recommended dose every day is the 0.01-2000mg compound, and this dosage can use or the fractionated dose use by dose.Can be generally the amount of the compound that produces curative effect with the absorption of active ingredient that carrier substance is mixed and made into the dose medicament.
Aspect given patient's result of treatment, produce the most effective result's accurate administration time and/or activity, pharmacokinetics and the bioavailability that the composition consumption depends on specific compound; Patient's physiological situation (comprise age, sex, disease type and stage, general physical condition, to the reactivity and the medication type of given dose), administration path etc.But above policy can be used as the basis of methods of treatment being carried out accurate adjustment, for example determines best time and/or dosage, only need carry out day-to-day test, comprises dosage and/or arrangement of time are monitored and adjusted to individuality.
Phrase used herein " pharmaceutically acceptable " refers to that those are in rational medical judgment scope, be suitable for being used for contacting people and animal tissues, and inexcessive toxigenicity, stimulation, anaphylaxis or other problem or complication have part, material, composition and/or the formulation of rational interests/risk ratio.
Term used herein " pharmaceutically acceptable carrier " refers to pharmaceutically acceptable material, composition or carrier, for example liquid or solid weighting agent, thinner, vehicle, solvent or capsule material.Each carrier must be " acceptable ", promptly with formulation in other composition compatible, harmless to patient.Some examples that can be used as the material of pharmaceutically acceptable carrier comprise: (1) sugar, as lactose, dextrose plus saccharose; (2) starch is as beta-cyclodextrin W-Gum, yam starch and replacement or unsubstituted; (3) Mierocrystalline cellulose and derivative thereof are as Xylo-Mucine, ethyl cellulose and cellulose acetate; (4) tragacanth gum powder; (5) Fructus Hordei Germinatus; (6) gelatin; (7) talcum; (8) vehicle is as theobroma oil and suppository wax (suppository waxes); (9) oil is as peanut oil, Oleum Gossypii semen, Thistle oil, sesame oil, sweet oil, Semen Maydis oil and soybean oil; (10) dibasic alcohol is as propylene glycol; (11) polyvalent alcohol is as glycerine, Sorbitol Powder, N.F,USP MANNITOL and polyoxyethylene glycol; (12) ester is as ethyl oleate and Laurate ethyl; (13) agar; (14) buffer reagent is as magnesium hydroxide and aluminium hydroxide; (15) Lalgine; (16) first pyrogen water; (17) isotonic saline solution; (18) Ringer's solution; (19) ethanol; (20) phosphate buffer soln; (21) other is used for the nontoxic compatible substances of pharmaceutical dosage form.In some embodiment, pharmaceutical composition of the present invention is pyrogen-free, that is, use Shi Buhui to patient and cause tangible fervescence.
Term " pharmacy acceptable salt " refers to the inorganic acid addition salt and the organic acid addition salt of the inhibitor of unit's poison relatively.These salt can inhibitor is separated at last with purifying during original place preparation, or, separate formed salt and prepare by respectively with purifying inhibitor and the appropriate organic or the inorganic acid reaction of free alkali form.Representational salt comprises hydrobromate, hydrochloride, vitriol, hydrosulfate, phosphoric acid salt, nitrate, acetate, valerate, oleate, palmitate, stearate, lauroleate, benzoate, lactic acid salt, phosphoric acid salt, tosylate, Citrate trianion, maleate, fumarate, succinate, tartrate, naphthoate (naphthylate), mesylate, gluconate, Lactobionate, dodecane sulfonate and amino acid salts etc.(for example referring to (1977) such as Berge " salt pharmaceutically ", J.Pharm.Sci.66:1-19).
Under other situation, the inhibitor that is used for the inventive method can contain one or more acidic functionality, can form pharmacy acceptable salt with pharmaceutically acceptable alkali like this.In these cases, term " pharmacy acceptable salt " refers to the mineral alkali and the organic bases additive salt of nontoxic relatively inhibitor.These salt equally can inhibitor is separated at last with purifying during original place preparation, or by respectively the purifying inhibitor of free acid form and suitable alkali (as oxyhydroxide, carbonate or the supercarbonate of pharmaceutically acceptable metallic cation), ammoniacal liquor or pharmaceutically acceptable organic primary amine, secondary amine or reactive tertiary amine being prepared.Typical an alkali metal salt or alkaline earth salt comprise lithium salts, sodium salt, sylvite, calcium salt, magnesium salts and aluminium salt etc.The typical organic amine that is used to form base addition salt comprises ethamine, diethylamine, quadrol, thanomin, diethanolamine, piperazine etc. (for example referring to, the document of above-mentioned Berge etc.).
In composition, can also there be wetting agent, emulsifying agent and lubricant (as sodium lauryl sulphate and Magnesium Stearate) and tinting material, releasing agent, coating material, sweeting agent, seasonings and spices, sanitas and antioxidant.
Pharmaceutically acceptable antioxidant comprises: (1) water soluble antioxidant, as xitix, cysteine hydrochloride, sodium pyrosulfate, pyrosulphite hydrogen sodium, S-WAT etc.; (2) oil-soluble inhibitor is as the anti-bad blood ester of palmitinic acid, Butylated Hydroxyanisole (BHA), Butylated Hydroxytoluene (BHT), Yelkin TTS, propyl gallate, alpha-tocopherol etc.; (3) metal chelator is as citric acid, ethylenediamine tetraacetic acid (EDTA) (EDTA), Sorbitol Powder, tartrate, phosphoric acid etc.
Be suitable for oral formulation and can be capsule, cachet, pill, tablet, lozenge (, being generally sucrose, gum arabic or tragacanth gum), pulvis, granule based on seasonings; Aqueous or anhydrous solution or suspensoid; Or oil-in-water or water in oil emulsion liquor; Or elixir or syrup; Or pastille (use inert base, as gelatin and glycerine, or sucrose and gum arabic) and/or mouth wash shua etc., each all contains the inhibitor of the amount of pre-determining as activeconstituents.Composition can also use with bolus, electuary or paste.
Be used for oral solid dosage (capsule, tablet, pill, dragee, pulvis, granule etc.), activeconstituents is planted pharmaceutically acceptable carrier with one or more and is mixed, as Trisodium Citrate or secondary calcium phosphate; And/or following any: (1) weighting agent or extender, as starch, cyclodextrin, lactose, sucrose, glucose, N.F,USP MANNITOL and/or silicic acid; (2) tackiness agent is as carboxymethyl cellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and/or gum arabic; (3) wetting Agent for Printing Inks is as glycerine; (4) disintegrating agent is as agar, lime carbonate, potato or tapioca (flour), Lalgine, some silicate and yellow soda ash; (5) solution retarding agent is as paraffin; (6) absorb accelerator, as quaternary ammonium compound; (7) wetting agent is as acetyl ethanol and Zerol; (8) absorption agent is as kaolin and wilkinite; (9) lubricant is as talcum, calcium stearate, Magnesium Stearate, solid polyethylene glycol, sodium lauryl sulphate and their mixture; And (10) tinting material.With regard to capsule, tablet and pill, pharmaceutical composition can also contain buffer reagent.The solid constituent of similar type also can be used as soft, the hard-filled gelatin capsule that weighting agent is used to use lactose or vehicle such as lactose (milk sugars) and high-molecular weight polyoxyethylene glycol.
Can prepare tablet by compacting or mold pressing, optional one or more kind auxiliary agents that use.Can use tackiness agent (as gelatin or Vltra tears), lubricant, inert diluent, sanitas, disintegrating agent (as sodium starch glycolate or croscarmellose sodium), tensio-active agent or dispersion agent to prepare compressed tablets.Can prepare molded tablet by in suitable machine, the moistening powdery inhibitor mixed thing of inert diluent being carried out mold pressing.
Other solid dosages such as tablet and dragee, capsule, pill and granule can be randomly with dressing and shell (other dressing of knowing as enteric coating and pharmacy field) cut (scored) or preparation.Can also prepare so that use therein activeconstituents is carried out slowly-releasing or controlled release them, for example, use Vltra tears, other polymeric matrix, liposome and/or the microsphere of different ratios, so that the target releasing pattern to be provided.Can form the sterilization composition form by such as they being sterilized, can be dissolved in other aseptic injection medium of sterilized water or some before use soon with holding to stay biofilter to filter or be used in combination sterilant.These compositions can also randomly contain opalizer, and composition can be only (or preferred) in GI privileged site release of active ingredients (optional slowly-releasing mode).The spendable example of imbedding composition comprises polymkeric substance and wax.If desired, activeconstituents also can form microencapsulation form with above-mentioned one or more kind vehicle.
Liquid dosage form for oral use comprises pharmaceutically acceptable emulsion, microemulsion, solution, suspensoid, syrup and elixir.Except that activeconstituents, can contain this area inert diluent commonly used in the liquid dosage form, for example water or other solvent; Stablizer and emulsifying agent, for example ethanol, Virahol, ethyl-carbonate, ethyl acetate, benzylalcohol, peruscabin, propylene glycol, 1, the fatty acid ester of 3-butyleneglycol, oil (particularly Oleum Gossypii semen, peanut oil, Semen Maydis oil, germ oil, sweet oil, Viscotrol C and sesame oil), glycerine, tetrahydrofurfuryl carbinol, polyoxyethylene glycol and sorbitan, and their mixture.
Except that inert diluent, this type of oral compositions also can comprise an agent, as wetting agent, emulsifying agent and suspensoid, sweeting agent, seasonings, tinting material, essence and sanitas.
Except that activeconstituents, suspensoid can contain suspensoid, for example ethoxylation isooctadecanol, polyoxyethylene sorbitol and sorbitan ester, Microcrystalline Cellulose, aluminium hydroxide, wilkinite, agar and tragacanth gum partially, and their mixture.
The formulation that rectum and vagina administration are used can be a suppository, can suitable nonirritant excipient or carrier (for example comprising theobroma oil, polyoxyethylene glycol, suppository wax or salicylate) be mixed with by one or more being planted inhibitor and one or more kinds, it at room temperature is a solid, but be liquid under body temperature, therefore will in rectum or vagina, melt and release bioactive agent.
The formulation that is suitable for vagina administration also comprises vaginal suppository, tapon (tampons), ointment, gelifying agent, paste, foaming agent or aerosol, contains suitable carriers known in the art.
The formulation that is used for part or transdermal administration inhibitor comprises pulvis, sprays, salve, paste, ointment, lotion, gelifying agent, solution, patch and inhalation.Active ingredient can be under aseptic condition and pharmaceutically acceptable carrier and any sanitas that may need, buffer reagent or propellant mixing.
Except that inhibitor, salve, paste, ointment and gelifying agent can contain vehicle, as animals and plants fat, oil, wax, paraffin, starch, tragacanth gum, derivatived cellulose, polyoxyethylene glycol, silicone, wilkinite, silicic acid, talcum and zinc oxide, or their mixture.
Except that inhibitor, pulvis and sprays can contain vehicle, as lactose, talcum, silicic acid, aluminium hydroxide, Calucium Silicate powder and Silon, or the mixture of these materials.Sprays can contain common propelling agent in addition, does not replace hydrocarbon (as butane and propane etc.) as chlorofluorocarbon and volatility.
Perhaps can give inhibitor by aerosol.This realizes by aqueous aerosol, Liposomal formulation or solid particulate that preparation contains said composition.Can use no water suspension (as fluorocarbon propellant).Preferred sound wave atomizer (sonic nebulizer), admittedly the preparation that is exposed under shearing for them reaches minimum, shearing can cause the degraded of compound.
Normally, by the aqueous solution or the suspension of reagent are prepared the preparation aqueous aerosol with the pharmaceutically acceptable carrier and the stablizer of routine.Carrier and stablizer change according to the needs of particular composition, but the typical case comprises nonionogenic tenside (Tweens, pluronics, sorbitan ester class, Yelkin TTS, hydrogenated castor oils), pharmaceutically acceptable latent solvent (as amino acid, buffer reagent, salt, carbohydrate or sugar alcohols such as harmless protein such as polyoxyethylene glycol, serum albumin, oleic acid, glycine).Aerosol is generally prepared by isotonic solution.
The additional benefit of transdermal patch is to health sustained release inhibitor.This formulation can prepare by making agent dissolves or being scattered in the suitable medium.Also can use absorption enhancer to increase the flux of transdermal inhibitor.Can be by the speed control film being provided or making inhibitor be scattered in this rate flux of control in polymeric matrix or the gel.
The pharmaceutical composition of the present invention that is applicable to the gi tract external administration contains one or more kind inhibitor of planting pharmaceutically acceptable aseptic aqueous solution or non-aqueous solution, dispersion agent, suspensoid or emulsion or sterile powder combination with one or more, it can form aseptic Injectable solution or dispersion liquid before use soon again, can contain antioxidant, buffer reagent, fungistat, make preparation and the isoosmotic solute of blood or suspensoid or the thickening material of intending being subjected to medicine.
The spendable suitable aqueous carrier and the example of nonaqueous carrier comprise in the pharmaceutical composition of the present invention: injectable organic esters such as water, ethanol, polyvalent alcohol (for example glycerine, propylene glycol, polyoxyethylene glycol etc.) and suitable mixture thereof, olive wet goods vegetables oil, ethyl oleate.By using coating material such as Yelkin TTS, keep the granular size in the dispersion liquid and using mode such as tensio-active agent can keep suitable flowability.
These compositions can also contain adjuvant, as sanitas, wetting agent, emulsifying agent and dispersion agent.Can guarantee to prevent that by using various antibacterial agents and anti-mycotic agent (for example p-Hydroxybenzoate, trichloro-butyl alcohol, phenol Sorbic Acid (phenol sorbic acid) etc.) microorganism from working.Also preferably in composition, comprise tension regulator, as carbohydrate, sodium-chlor etc.In addition, the absorption that can prolong medical injection by the reagent that uses aluminum monostearate and gelatin etc. to postpone absorption.
Sometimes, in order to prolong drug effect, preferably slow down absorption to subcutaneous injection or intramuscular injection medicine.For example with medicine dissolution or be suspended in the vehicle oil to postpone absorption to the medicine of parenteral administration.
Prepare injectable prolonged action preparation by making inhibitor in polylactide-biodegradable polymers such as poly-glycollide, form microcapsule matrix.According to the ratio of medicine and polymkeric substance, the character of employed concrete polymkeric substance, can control the release rate of medicine.The example of other biodegradable polymer comprises poe and poly-acid anhydrides.Medicine can also be embedded in liposome compatible or the micro emulsion with the preparation long acting injection with body tissue.
The mode that gives preparation can give for oral, parenteral administration, topical administration or per rectum.Certainly, for each bar route of administration, all with suitable formulation administration.For example, give sheet or pharmaceutical capsules with injection, inhalation, eye wash, salve, suppository, infusion solution form; With lotion or salve form topical and with the suppository form rectal administration.Preferred oral.
Phrase used herein " gi tract external administration " refers to be different from the mode of administration of interior administration of intestines and topical, be generally drug administration by injection, include but not limited in intravenous, intramuscular, endarterial, the sheath, in the capsule, the socket of the eye, intracardiac, intracutaneous, endoperitoneal, that wear sheath, subcutaneous, subepidermal, IA, subcapsular, subarachnoid, intravertebral and intrasternal injection and transfusion.
Phrase used herein " whole body administration " and " peripherally administered " refer to directly part, medicine or other material not fed central nervous system, thereby carry out metabolism and other similar process so that enter patient's whole body, for example, and subcutaneous administration.
Can use these inhibitor to people and other animal by any suitable route of administration, treat, comprise that through port is attached, nose administration (for example with Sprayable), administration and topical in rectal administration, vagina administration, gi tract external administration, the brain pond (with pulvis, salve or drops form) comprise through cheek administration, sublingual administration.
No matter select which kind of route of administration, can utilize the known ordinary method of one skilled in the art that inhibitor of the present invention (hydrate forms that can be suitable uses) and/or pharmaceutical composition are mixed with pharmaceutically acceptable formulation.
The actual dose level of activeconstituents can change in the pharmaceutical composition of the present invention, thereby for particular patient, absorption of active ingredient, combination and administering mode can effectively be realized desirable therapeutic response, and nontoxic to patient.
The concentration of disclosure compound in pharmaceutically acceptable mixture changes along with some factors.These factors comprise the pharmacokinetic characteristic and the route of administration of the application dosage of compound, employed compound.Usually, the present composition can be the aqueous solution of parenteral administration, contains the 0.1-10%w/v disclosure compound of having an appointment, and other material.Typical dosage range is the about 50mg/kg body weight of about 0.01-every day, gives with 1-4 fractionated dose.The The compounds of this invention that each fractionated dose contained can be identical or different.Effective dose depends on some factors such as the formulation of the total health situation that comprises patient and selected compound and route of administration.
Another aspect of the present invention provides a kind of combined therapy, wherein one or more is planted other therapeutical agent and proteinase inhibitor and uses jointly.This combined treatment can be by simultaneously, continuously or the mode that quantitatively gives single treatment component respectively realize.
In some embodiment, The compounds of this invention is used in combination with chemotherapeutic.Suitable chemotherapeutic can comprise natural product, as catharanthus alkaloid (promptly, vinealeucoblastine(VLB), vincristine(VCR), Vinorelbine), taxol, epipodophyllotoxin (promptly, etioposide, teniposide), microbiotic (actinomycin (dactinomycin), daunorubicin (daunorubicin), Zorubicin and darubicin (idarubicin)), anthracycline (anthracyclines), mitoxantrone (mitoxantrone), bleomycin (bleomycins), Plicamycin (plicamycin) (Plicamycin (mithramycin)) and mitomycin (mitomycin), enzyme (altheine enzyme, altheine is carried out system's metabolism, deprive the cell that does not have synthetic self l-asparagine of ability); Anti-platelet agents; Antiproliferative/antimitotic alkylating agent, as nitrogen mustard (mustargen, endoxan and analogue, melphalan, Chlorambucil), ethylenimine and first melamine (methylmelamines) (hexamethyl melamine and thio-tepa (thiotepa)), alkyl sulfonate esters (busulfan (busulfan)), nitrosourea (carmustine (carmustine, BCNU) and analogue, U-9889), trazenes-Dacarbazine (dacarbazinine) (DTIC); Antiproliferative/antimitotic metabolic antagonist is as folacin (amethopterin (methotrexate)), pyrimidine analogue (Fluracil (fluorouracil), floxuridine (floxuridine) and cytosine arabinoside (cytarabine)), purine analogue and relevant inhibitor (mercaptopurine (mercaptopurine), Tioguanine (thioguanine), pentostatin (pentostatin) and 2-chlorine Deoxyadenosine); Aromatase inhibitor (Anastrozole (anastrozole), Exemestane (exemestane) and letrozole (letrozole)); And platinum coordination complex (cis-platinum (cisplatin), NSC-241240 (carboplatin)), procarbazine (procarbazine), hydroxyurea, Ortho-para-prism DDD (mitotane), aminoglutethimide (aminoglutethimide); Hormone (that is, oestrogenic hormon) and trop(h)ic hormone are as interstitialcellstimulating hormone (ICSH) liberin (LHRH) agonist (Coserelin (goserelin), leuprorelin acetate (leuprolide) and triptorelin (triptorelin)).Other chemotherapeutic can comprise mustargen (mechlorethamine), camptothecine, ifosfamide (ifosfamide), tamoxifen (tamoxifen), raloxifene (raloxifene), gemcitabine (gemcitabine), Vinorelbine (navelbine), or any analogue or the derivative of aforesaid compound.
In some embodiment, The compounds of this invention is used in combination with steroid.Suitable steroid can include, but are not limited to the 21-prebediolone acetate, Modrasone (alclometasone), alphasone, amcinonide (amcinonide), beclometasone (beclomethasone), Betamethasone Valerate (betamethasone), budesonide (budesonide), chlorine prednisone (chloroprednisone), clobetasol (clobetasol), clocortolone (clocortolone), Syntestan (cloprednol), Kendall compound, cortisone (cortisone), cortivazol (cortivazol), deflazacort (deflazacort), desonide (desonide), desoximetasone (desoximetasone), dexamethasone (dexamethasone), diflorasone (diflorasone), Vecort (diflucortolone), difluprednate (difuprednate), glycyrrhetinic acid (enoxolone), fluorine
Mi Song (fluazacort), Topilar (flucloronide), fluorine compound (flumethasone), flunisolide (flunisolide), fluocinonide (fluocinoloneacetonide), fluocinolone acetonide (fluocinonide), fluocortin butyl (fluocortin butyl), fluocortolone (fluocortolone), flurrenolone (fluorometholone), fluperolone acetate (fluperolone acetate), StL-1106 (fluprednidene acetate), fluprednisolone (fluprednisolone), flurrenolone (flurandrenolide), Fluticasone Propionate (fluticasone propionate), fluderma (formocortal), halcinonide (halcinonide), Halobetasol Propionate (halobetasol propionate), halometasone (halometasone), hydrocortisone (hydrocortisone), loteprednol (loteprednol etabonate), mazipredone (mazipredone), medroxyprogesterone (medrysone), Methyllprednisolone (meprednisone), methyl meticortelone (methylprednisolone), Mometasone Furoate (mometasone furoate), dillar (paramethasone), Po Nikasong (prednicarbate), Ultracortene-H (prednisolone), Ultracortene-H 25-diethylin acetic ester (prednisolone 25-diethylaminoacetate), prednisolone phosphate sodium (prednisolone sodiumphosphate), prednisone (prednisone), W-4869 (prednival), methylene prednisolone (prednylidene), trimexolone (rimexolone), sulphur hydrocortisone (tixocortol), triamcinolone (triamcinolone), triamcinolone (triamcinolone acetonide), Triamcinolone Benetonide (triamcinolonebenetonide), TATBA (triamcinolone hexacetonide), and their salt and/or derivative.
In some embodiment, The compounds of this invention is used in combination with immunotherapeutic agent.Suitable immunotherapeutic agent can include, but are not limited to S-Neoral (cyclosporine), thalidomide (thalidomide) and monoclonal antibody.Monoclonal antibody can be naked or put together, as Rituximab (rituximab), tositumomab (tositumomab), Allan monoclonal antibody (alemtuzumab), epratuzumab (epratuzumab), ibritumomab tiuxetan (ibritumomab tiuxetan), lucky trastuzumab azoles rice star (gemtuzumabozogamicin) difficult to understand, rhuMAb-VEGF (bevacizumab), Cetuximab (cetuximab), erlotinib (erlotinib) and Herceptin (trastuzumab).
Embodiment
Scheme 1: embodiment's 1 is synthetic
Synthesizing (B)
The NBoc leucine (50.0mmol, 11.56g) and phenylalanine methyl ester (50.0mmol, add in DMF 10.78g) (500mL) solution HOBT (10.81g, 80.0mmol) and DIEA (200.0mmol, 25.85g, 35mL).In ice bath, mixture is cooled to 0 ℃, and gradation adding BOP in 5 minutes (80.0mmol, 35.38g).Reaction solution places under the Ar Pressure, and stirring is spent the night.Reaction solution dilutes with salt solution (1000mL), and (5 * 200mL) extract with ethyl acetate.Merge organic layer, water (10 * 100mL) and salt solution (2 * 150mL) wash, through dried over mgso.Filter and remove sal epsom, decompression removes volatile matter, obtains (A) (18.17g).In 0 ℃ of refrigerative 80%TFA/DCM of 50mL solution, add BocNHLeuPheOMe (45.86mmol, 18.0g).Stirred solution makes it to rise to room temperature in 2 hours.Decompression removes volatile matter, obtains oil.In this oil, add BocNHhPhe (45.86mmol, 12.81g), DMF (500mL), HOBT (73.37mmol, 9.91g) and DIEA (183.44mmol, 23.70g, 32.0mL).In ice-water bath, mixture is cooled to 0 ℃, and gradation adding BOP in 5 minutes (73.37mmol, 32.45g).Reaction solution placed under the argon gas spend the night, make it to rise to room temperature.Reaction solution water (1500mL) dilutes, and (5 * 300mL) extract with DCM.Merge organic layer, water (6 * 300mL) and salt solution (1 * 300mL) washs, through dried over mgso.Filter and remove sal epsom, decompression removes volatile matter, obtains yellow solid.In this solid, add 200mL 95% ethanol, heated mixt to 65 ℃ so that solid all dissolve.In solution, add the 1000mL refrigerated water then, collect the gained throw out, obtain (B) (21.59g).
Synthesizing (C)
(1.47mmol 0.81g) mixes with TFA/DCM (80%), stirs under the room temperature 1 hour, and this moment, enriched mixture and was placed 2 hours under high vacuum, generated the tfa salt of three peptamines (Q) with compound (B).In 0 ℃ of solution of the DMF of tfa salt (1.47mmol) (10mL), add DIEA (4.4mmol, 0.77mL), add then the benzyloxy Acetyl Chloride 98Min. (2.21mmol, 0.343mL).Under a nitrogen pressure, stirring reaction liquid 2 hours makes it to room temperature.Mixture is with salt solution (15mL) dilution, with ethyl acetate extraction (3 * 15mL).Merge organic layer, water (2 * 15mL) and salt solution (1 * 15mL) washs, through dried over sodium sulfate.Removal of sodium sulfate by filtration, decompression removes volatile matter.Thick material obtains (C) (0.83g) through purification by flash chromatography.
Synthesizing (D)
Be cooled to 0 ℃ (C) (1.38mmol, methanol 0.830g) (3: 1,28mL) add in the suspension lithium hydroxide (13.8mmol, 0.331g).After 18 hours, under 5 ℃, make the reaction quencher, further with the dilution of 150mL water with the 20mL saturated ammonium chloride.With the pH to 2 of 1N hydrochloric acid conditioned reaction mixture, solid collected by filtration obtains (D) (0.900g).
Synthesizing (E)
(0.17mmol 0.10g) is dissolved in the methyl alcohol (10mL), and (5%, 0.08g), under a hydrogen-pressure, stirred reaction mixture is 2 hours under the room temperature to add Pd-C with compound (D).Use the argon purge mixture then,, concentrate and obtain (E) through diatomite filtration.
Compound
1Synthetic
Stir down, to (F) (see: Bioorg.Med.Chem.Letter 1999,9,2283-88) add in the DMF of (0.164mmol) (2mL) solution (E) (0.17mmol), DIEA (0.652mmol, 0.114mL) and HOBT (0.266mmol, 0.036g).In ice bath, mixture is cooled to 0 ℃, and gradation adding BOP (0.262mmol, 0.116g).Under an Ar Pressure, stir the mixture under 5 ℃ and spend the night.Reaction solution is used ethyl acetate extraction with salt solution (15mL) dilution.Organic layer water, saturated sodium bicarbonate and salt water washing are through anhydrous magnesium sulfate drying.Remove by filter sal epsom, decompression removes volatile matter.With the thick material of preparation HPLC purifying, obtain compound 1 (IC
5020S CT-L＜50nM, IC
50Based on the CT-L of cell＜100nM).
Scheme 2: embodiment
2Synthetic
Synthesizing (G)
(1.0mmol 0.601g) is dissolved in the methyl alcohol (25mL), and (10%, 600mg), under a hydrogen-pressure, stirred reaction mixture is 48 hours under the room temperature to add Pd-C with compound (C).Use the argon purge mixture then,, concentrate and obtain (G) (600mg) through diatomite filtration.
Synthesizing (H)
0 ℃ (G) (1.0mmol, add in DCM 0.511g) (40mL) solution DIEA (2.0mmol, 0.348mL) and DBPCI (2.0mmol, 0.593g).Under a nitrogen pressure, under the room temperature, stirring reaction liquid spends the night.Vacuum concentration reaction solution then, thick material obtains (H) (0.181g) through purification by flash chromatography.
Synthesizing (I)
Be cooled to 0 ℃ (H) (0.11mmol, methanol 0.090g) (3: 1,4mL) add lithium hydroxide (1.6mmol, 0.4mL, the 4M aqueous solution) in the suspension.After 45 minutes, under 5 ℃, make the reaction quencher with the 10mL saturated ammonium chloride.PH to 2 with 1N hydrochloric acid conditioned reaction mixture uses ethyl acetate extraction.Organic layer is through water and salt water washing, through anhydrous magnesium sulfate drying.Remove by filter sal epsom, decompression removes volatile matter, obtains (I).
Synthesizing (J)
Stir down, (see: Bioorg.Med.Chem.Letter 1999,9 to (F), 2283-88) add (I) (0.082mmol in the DMF of (0.082mmol) (2mL) solution, 0.062g), DIEA (0.328mmol, 0.057mL) and HOBT (0.133mmol, 0.018g).In ice bath, mixture is cooled to 0 ℃, and gradation adding BOP (0.131mmol, 0.058g).Under an Ar Pressure, stir the mixture under 5 ℃ and spend the night.Reaction solution water (15mL) dilution is filtered collection and is obtained (J) (0.081g).
Compound
2Synthetic
(0.005mmol adds 4 and drips and 10%Pd/C (5mg) in THF 0.005g) (1mL) solution at (J).Under hydrogen, stirred the mixture under the room temperature 1 hour, use diatomite filtration, handle filtrate with yellow soda ash (0.263g is dissolved in 3mL water).Solid collected by filtration is placed in the high vacuum, obtains compound
2(0.004g).
Scheme 3: embodiment
3Synthetic
Synthesizing (L)
At (K) (0.19mmol, 0.10g) THF (20mL) solution in add potassiumiodide (0.038mmol, 0.0063g), dimethylamine (0.456mmol, 0.228mL, 2M TFH solution), under a nitrogen pressure, stir the mixture and spend the night, decompression removes volatile matter, and thick material absorbs with ethyl acetate (15mL), water (2 * 10mL) and salt solution (2 * 10mL) washing, through dried over mgso.Remove by filter sal epsom, decompression removes volatile matter, obtains (L) (0.100g).
Synthesizing (M)
Be cooled to 0 ℃ (L) (0.186mmol, methanol 0.100g) (3: 1,4mL) add in the suspension lithium hydroxide (1.86mmol, 0.045g).After 12 hours, under 5 ℃, make the reaction quencher, further with the dilution of 10mL water with the 20mL saturated ammonium chloride.With the pH to 3 of 1N hydrochloric acid conditioned reaction mixture, (3 * 15mL) extractions are through dried over mgso with chloroform.Remove by filter sal epsom, decompression removes volatile matter, obtains (M).
Compound
3Synthetic
Stir down, to (F) (see: Bioorg.Med.Chem.Letter 1999,9,2283-88) add in the DMF of (0.082mmol) (1mL) solution (M) (0.021mmol), DIEA (0.28mmol, 0.05mL) and HOBT (0.133mmol, 0.018g).In ice bath, mixture is cooled to 0 ℃, and gradation adding BOP (0.131mmol, 0.058g).Under an Ar Pressure, stir the mixture under 5 ℃ and spend the night.Use salt solution (15mL) dilute reaction solution then, use ethyl acetate extraction.Organic layer water, saturated sodium bicarbonate and salt water washing are through anhydrous magnesium sulfate drying.Remove by filter sal epsom, decompression removes volatile matter.Obtain compound
3(IC
5020S CT-L＜100nM is based on the CT-L of cell＜100nM).
Scheme 4: embodiment
4Synthetic
Synthesizing (N)
(1.80mmol 1.0g) mixes with TFA/DCM (80%), stirs under the room temperature 1 hour, and this moment, enriched mixture and was placed 2 hours under high vacuum, generated the tfa salt of three peptamines with compound (B).In the DMF of 0 ℃ tfa salt (1.80mmol) (10mL) solution, add DIEA (3.6mmol, 0.7mL), add then chloroacetyl chloride (2.7mmol, 0.215mL).Under a nitrogen pressure, stirring reaction liquid spends the night, and makes it to room temperature.Mixture is with salt solution (15mL) dilution, with ethyl acetate extraction (3 * 15mL).Merge organic layer, water (2 * 15mL) and salt solution (2 * 15mL) wash, through dried over sodium sulfate.Removal of sodium sulfate by filtration, decompression removes volatile matter.Thick material is suspended in the ethyl acetate, filters and obtains (N) (0.640g).
Synthesizing (O)
At (N) (0.094mmol, 0.050g) THF (10mL) solution in add potassiumiodide (0.019mmol, 0.0032g) and piperidines (0.113mmol, 0.0096g), under a nitrogen pressure, stir the mixture and spend the night, decompression removes volatile matter, thick material absorbs with ethyl acetate (15mL), water (2 * 10mL) and salt solution (2 * 10mL) wash, through dried over mgso.Remove by filter sal epsom, decompression removes volatile matter, obtains (O).
Synthesizing (P)
Be cooled to 0 ℃ (O) (0.094mmol) methanol (3: 1,4mL) add in the suspension lithium hydroxide (0.94mmol, 0.023g).After 12 hours, under 5 ℃, make the reaction quencher, further with the dilution of 10mL water with the 20mL saturated ammonium chloride.With the pH to 3 of 1N hydrochloric acid conditioned reaction mixture, (3 * 15mL) extractions are through dried over mgso with DCM.Remove by filter sal epsom, decompression removes volatile matter, obtains (P).
Compound
4Synthetic
Stir down, (see: Bioorg.Med.Chem.Letter 1999,9 to (F), 2283-88) add (P) (0.082mmol in the DMF of (0.082mmol) (2mL) solution, 0.046g), DIEA (0.328mmol, 0.057mL) and HOBT (0.133mmol, 0.018g).In ice bath, mixture is cooled to 0 ℃, and gradation adding BOP (0.131mmol, 0.058g).Under an Ar Pressure, stir the mixture under 5 ℃ and spend the night.Ethyl acetate extraction is used in reaction solution water (15mL) dilution.Organic layer water, saturated sodium bicarbonate and salt water washing are through first water magnesium sulfate drying.Remove by filter sal epsom, decompression removes volatile matter.Obtain compound
4(0.034g) (IC
5020SCT-L＜100nM, IC
50Based on the CT-L of cell＜100nM).
Scheme 5: embodiment
5Synthetic
Synthesizing (T)
Except replacing (F) with (Q), replace (E) with cyclopropyl acetate, obtain compound (T) according to the step that (E) is changed into 1 substantially.
Synthesizing (U)
Except replacing (C), obtain compound (U) according to the step that (C) is changed into (D) substantially with (T).
Compound
5Synthetic
Except replacing (E), substantially according to (E) changed into (U)
1Step obtain compound
5
Scheme 6: embodiment
6Synthetic
Synthesizing (W)
(0.25g 0.39mmol) mixes with 12mL TFA/DCM (80%), stirs under the room temperature 1 hour, and this moment, enriched mixture and was placed 2 hours under high vacuum, generated the tfa salt of three peptamines with compound (V).Thick amine salt is dissolved among the 6mL DMF, add 2-morpholino acetate (0.074g, 0.507mmol), add then DIEA (0.504g, 0.68mL, 3.90mmol).In ice bath mixture is cooled to 0 ℃, (0.32g, 0.62mmol), under an Ar Pressure, stirring reaction liquid spends the night, and makes it to room temperature to add PyBOP.Mixture is with salt solution (50mL) dilution, with ethyl acetate extraction (5 * 20mL).Merge organic layer, with saturated sodium bicarbonate (5 * 15mL) and salt solution (1 * 25mL) washs, through dried over mgso.Filter and remove sal epsom, decompression removes volatile matter and obtains ester intermediate (0.195g).(0.150g, 0.23mmol) the middle mixture that successively adds Pd/C (0.05g) and 5mL methyl alcohol and ethyl acetate (1: 1) is positioned over mixture under the hydrogen-pressure at the ester intermediate.After 2 hours, with a stopper diatomite filtration content, vacuum concentration obtains (W) (0.12g).
Compound
6Synthetic
Stir down, (see: Bioorg.Med.Chem.Letter 1999,9,2283-88) (1.3 equivalents to (F), 0.27mmol, 0.083mg) formonitrile HCN (5mL) solution in add (W) (1 equivalent, 0.17mmol, 0.10g), DIEA (10 equivalents, 1.73mmol, 0.30mL) and HOBT (1.6 equivalents, 0.27mmol, 0.037mg).In ice bath, mixture is cooled to 0 ℃, and gradation adding PyBOP (1.6 equivalents, 0.27mmol, 0.14g).Under an Ar Pressure, stir the mixture under 5 ℃ and spend the night.Use the saturated sodium-chloride dilute reaction solution then, use ethyl acetate extraction.Organic layer water and salt water washing through anhydrous magnesium sulfate drying, are condensed into one.Thick material is dissolved in the methyl alcohol of minimum, slowly adds in 0 ℃ of refrigerated water (100mL) of rapid stirring, obtain compound by filtering separation then
6(0.080g).
Scheme 7: embodiment
7Synthetic
Synthesizing (X)
In formonitrile HCN (900mL) solution of NBoc leucine (19.81g, 85.67mmol, 1.0 equivalents) and phenylalanine benzyl ester (25.0g, 85.67mmol, 1.0 equivalents), add and DIEA (44.29g, 60mL, 342.68mmol, 4.0 equivalents).In ice bath, mixture is cooled to 0 ℃.Add HOBT (18.52g, 137.08mmol, 1.6 equivalents) in this mixture, gradation adds PyBOP (71.33g, 137.08mmol, 1.6 equivalents) in 5 minutes then.Reaction solution is placed under the Ar Pressure, and stirring is spent the night.Decompression removes volatile matter, and remaining material is by the 500mL up in ethyl acetate, with saturated sodium bicarbonate, water and salt water washing, through dried over mgso.Filter and remove sal epsom, volatile matter is removed in decompression, obtains (X).
Synthesizing (Y)
In 0 ℃ of refrigerative 70%TFA/DCM (150mL) solution, add (X) (25.0g, 53.35mmol, 1.0 equivalents).In 2 hours, to stir this solution, and make it to room temperature, this moment, enriched mixture and was placed under high vacuum 2 hours, generated the tfa salt of two peptamines.In resulting oil, add BocNHhPhe (14.68g, 53.35mmol, 1.0 equivalents), 550mL formonitrile HCN and DIEA (27.58g, 37.2mL, 213.4mmol, 4.0 equivalents), in ice bath, mixture is cooled to 0 ℃.Add HOBT (11.53g, 85.36mmol, 1.6 equivalents) in the refrigerative mixture, gradation adds PyBOP (44.42g, 85.36mmol, 1.6 equivalents) in 5 minutes then.Under the argon gas, the reaction solution placement is spent the night, make it, form white depositions this moment to room temperature.Reaction mixture, solid collected by filtration with cold formonitrile HCN washing, obtains (Y) (24.86g) then.
Synthesizing (Z)
(0.023mol 14.5g) mixes with TFA/DCM (80%), stirs under the room temperature 1 hour, and this moment, enriched mixture and was placed 2 hours under high vacuum, generated the tfa salt of three peptamines with compound (Y).In formonitrile HCN (120mL) solution of tfa salt (0.023mol, 1 equivalent), add the 4-chlorobutanoylchloride (1.2 equivalents, 0.028mol, 0.32mL) and DIEA (4 equivalents, 0.092mol, 16mL).Stirred the mixture under the room temperature 2 hours, and concentrated and purifying by flash chromatography then, obtain (Z) (8g).
Synthesizing (AA)
(Z) (1 equivalent, 0.095mmol, add in anhydrous propanone 60mg) (8mL) solution sodium iodide (5 equivalents, 0.47mmol, 70.5mg).Under a nitrogen pressure, stir the mixture under the reflux conditions and spend the night.Concentrated reaction mixture is to doing then, and residue absorbs with DCM.Organic layer water and salt water washing through anhydrous magnesium sulfate drying, concentrate and obtain yellow solid (AA) (50mg).
Synthesizing (BB)
(30mg adds dimethylamine (1.2 equivalents, 0.05mmol, 2M THF solution, 25 μ L) and DIEA (1 equivalent, 0.041mmol, 7.2 μ L) in THF 0.041mmol) (2mL) solution at (AA).Stir the mixture under the room temperature and spend the night, be concentrated into dried.The residue up in ethyl acetate, water and salt water washing through anhydrous magnesium sulfate drying, concentrate and obtain the oily product.With thick ester be dissolved in methanol/ethyl acetate (1: 1,10mL) in, (5%, 20mg), under a hydrogen-pressure, stirred reaction mixture is 2 hours under the room temperature to add Pd-C.Use the argon purge mixture then,, concentrate and obtain (BB) (21mg) through diatomite filtration.
Compound
7Synthetic
Stir down, (see: Bioorg.Med.Chem.Letter 1999 to (F), 9,2283-88) (1.2 equivalents add (BB) (1 equivalent in DMF 0.054mmol) (3mL) solution, 0.045mmol, 21mg), DIEA (4 equivalents, 0.18mmol, 31 μ L) and HOBT (1.6 equivalents, 0.072mmol, 10mg).In ice bath, mixture is cooled to 0 ℃, and gradation adding PyBOP (1.6 equivalents, 0.072mmol, 37mg).Then under a nitrogen pressure, stir the mixture under 5 ℃ and spend the night.Reaction solution dilutes with saturated sodium-chloride, uses ethyl acetate extraction.Organic layer water and salt water washing through anhydrous magnesium sulfate drying, are concentrated into oil, and this oil obtains compound through purification by flash chromatography
7(16.7mg) (IC
5020S CT-L＜50nM is based on the CT-L of cell＜150nM).
Scheme 8: embodiment
8Synthetic
Synthesizing (CC)
With compound (Y) (1.55g, 0.0023mol) be dissolved in methanol/ethyl acetate (1: 1,40mL) in, add Pd-C (5%, 500mg).Under hydrogen, stirred the mixture under the room temperature 2 hours, then through diatomite filtration, concentrate and obtain the carboxylic acid intermediate.Stir down, (see: Bioorg.Med.Chem.Letter 1999,9,2283-88) (1.2 equivalents to (F), 2.55mmol, add in DMF 436mg) (50mL) solution carboxylic acid intermediate (1 equivalent, 2.12mmol, 1.24g), DIEA (4 equivalents, 8.48mmol, 1.5mL) and HOBT (1.6 equivalents, 3.39mmol, 458mg).In ice bath, mixture is cooled to 0 ℃, and gradation adding PyBOP (1.6 equivalents, 3.39mmol, 1.76g).Under a nitrogen pressure, stir the mixture under 5 ℃ and spend the night.Reaction solution dilutes with saturated sodium-chloride, uses ethyl acetate extraction.Organic layer water and salt water washing through anhydrous magnesium sulfate drying, are concentrated into oil, and this oil obtains (CC) (356mg) through purification by flash chromatography.
Compound
8Synthetic
(23.6mg 0.034mmol) mixes with TFA/DCM (80%), stirs under the room temperature 1 hour, and this moment, enriched mixture and was placed 2 hours under high vacuum, generated the tfa salt of tetrapeptide amine with compound (CC).Add 1,3 in the DCM of tfa salt solution, (1.2 equivalents, 0.041mmol 8.5mg) and TEA (4 equivalents, 0.136mmol, 26 μ L), at room temperature stir the mixture and spend the night 5-trimethylammonium-1-H-pyrazoles-4-SULPHURYL CHLORIDE.Concentrate crude mixture to doing the residue up in ethyl acetate.Organic layer water and salt water washing through anhydrous magnesium sulfate drying, are concentrated into oil, and this oil obtains compound through purification by flash chromatography
8(2mg) (IC
5020S CT-L＜100nM is based on the CT-L of cell＜100nM).
Scheme 9: embodiment
9Synthetic
Compound
9Synthetic
(63.7mg 0.092mmol) mixes with TFA/DCM (80%), stirs under the room temperature 1 hour, and this moment, enriched mixture and was placed 2 hours under high vacuum, generated the tfa salt of tetrapeptide amine with compound (CC).In the DCM of tfa salt solution, add phenylcarbimide (1.5 equivalents, 0.14mmol, 15 μ L) and DIEA (3 equivalents, 0.276mmol, 50 μ L), at room temperature stir the mixture and spend the night.Concentrate crude mixture to doing the residue up in ethyl acetate.Organic layer water and salt water washing through anhydrous magnesium sulfate drying, are concentrated into oil, and this oil obtains compound through purification by flash chromatography
9(2.8mg).
Scheme 10: embodiment
10Synthetic
Compound
10Synthetic
(48.5mg 0.07mmol) mixes with TFA/DCM (80%), stirs under the room temperature 1 hour, and this moment, enriched mixture and was placed 2 hours under high vacuum, generated the tfa salt of tetrapeptide amine with compound (CC).In the DCM of tfa salt solution, add thiocarbanil (1.5 equivalents, 0.105mmol, 20 μ L) and DIEA (3 equivalents, 0.21mmol, 40 μ L), at room temperature stir the mixture and spend the night.Concentrate crude mixture to doing the residue up in ethyl acetate.Organic layer water and salt water washing through anhydrous magnesium sulfate drying, are concentrated into oil, and this oil obtains compound through purification by flash chromatography
10(1mg).
Be equal to
Those skilled in the art will recognize, perhaps only use routine test just can determine compound and method that compound multiple and described here and application method thereof are equal to.This being equal to, be considered to fall within the scope of the present invention, and covered by following claim.
Above-cited all reference and publication here integral body are incorporated herein by reference.
Claims (63)
1. compound or its pharmacy acceptable salt with formula (I) structure,
Wherein each A independently is selected from C=O, C=S and SO
2Or
When adjacent with the Z that exists, A is optional to be covalent linkage;
L does not exist or is selected from C=O, C=S and SO
2, preferred L does not exist or is C=O;
M does not exist or is C
1-12Alkyl;
Q does not exist or is selected from O, NH and N-C
1-6Alkyl;
X is selected from O, NH and N-C
1-6Alkyl;
Y does not exist or is selected from O, NH and N-C
1-6Alkyl, S, SO, SO
2, CHOR
10And CHCO
2R
10
Each Z independently is selected from O, S, NH and N-C
1-6Alkyl; Or
When adjacent with the A that exists, Z is optional to be covalent linkage;
R
1, R
2, R
3And R
4Independently be selected from C separately
1-6Alkyl, C
1-6Hydroxyalkyl, C
1-6Alkoxyalkyl, aryl and C
1-6Aralkyl, any group are wherein randomly replaced by one or more acid amides, amine, carboxylic acid (or its salt), ester, mercaptan or thioether substituting group;
R
5Be N (R
6) LQR
7
R
6Be selected from hydrogen, OH and C
1-6Alkyl;
R
7Be selected from hydrogen, C
1-6Alkyl, C
1-6Thiazolinyl, C
1-6Alkynyl, aryl, C
1-6Aralkyl, heteroaryl, C
1-6Heteroaralkyl, R
8ZAZ-C
1-8Alkyl-, R
11Z-C
1-8Alkyl-, (R
8O) (R
9O) P (=O) O-C
1-8Alkyl-ZAZ-C
1-8Alkyl-, R
8ZAZ-C
1-8Alkyl-ZAZ-C
1-8Alkyl-(preferred R
8ZA-C
1-8Alkyl-ZAZ-C
1-8Alkyl-), heterocyclic radical MZAZ-C
1-8Alkyl-, (R
8O) (R
9O) P (=O) O-C
1-8Alkyl-, (R
10)
2N-C
1-12Alkyl-, (R
10)
3N
+-C
1-12Alkyl-, heterocyclic radical M-, carbocylic radical M-, R
11SO
2C
1-8Alkyl-and R
11SO
2NH; Or
R
6And R
7Common is C
1-6Alkyl-Y-C
1-6Alkyl, C
1-6Alkyl-ZAZ-C
1-6Alkyl, ZAZ-C
1-6Alkyl-ZAZ-C
1-6Alkyl, ZAZ-C
1-6Alkyl-ZAZ or C
1-6Alkyl-A forms ring thus;
R
8And R
9Independently be selected from hydrogen, metallic cation, C
1-6Alkyl, C
1-6Thiazolinyl, C
1-6Alkynyl, aryl, heteroaryl, C
1-6Aralkyl and C
1-6Heteroaralkyl is preferably selected from hydrogen, metallic cation and C
1-6Alkyl, or R
8And R
9Common is C
1-6Alkyl forms ring thus;
Each R
10Independently be selected from hydrogen and C
1-6Alkyl is preferably C
1-6Alkyl; And
R
11Independently be selected from hydrogen, C
1-6Alkyl, C
1-6Thiazolinyl, C
1-6Alkynyl, carbocylic radical, heterocyclic radical, aryl, heteroaryl, C
1-6Aralkyl and C
1-6Heteroaralkyl, condition are to work as R
6Be H or CH
3, and Q is not when existing, LR
7Not hydrogen, unsubstituted C
1-6Alkyl C=O, amino acid whose another chain, tertbutyloxycarbonyl (Boc), benzoyl (Bz), fluorenes-9-base methoxycarbonyl (Fmoc), trityl group (trityl), carbobenzoxy-(Cbz) (Cbz), trichloro-ethoxycarbonyl (Troc) or replace or unsubstituted aryl or heteroaryl; And
Under any situation that has a sequence ZAZ, having a member in this sequence at least must not be covalent linkage.
2. the described compound of claim 1, wherein R
1, R
2, R
3And R
4Independently be selected from C
1-6Alkyl and C
1-6Aralkyl.
3. the described compound of claim 2, wherein R
1And R
3Be C
1-6Aralkyl, and R
2And R
4Be C
1-6Alkyl.
4. the described compound of claim 3, wherein X is O, R
1Be 2-styroyl, R
2Be isobutyl-, R
3Be phenmethyl, R
4Be isobutyl-.
5. the described compound of claim 4, wherein L and Q do not exist, and R
6Be C
1-6Alkyl.
6. the described compound of claim 5, wherein R
7Be selected from C
1-6Alkyl, C
1-6Thiazolinyl, C
1-6Alkynyl, C
1-6Aralkyl and C
1-6Heteroaralkyl.
7. the described compound of claim 6, wherein R
7Be C
1-6Alkyl.
8. the described compound of claim 7, wherein R
7It is butyl.
9. the described compound of claim 6, wherein R
7Be C
1-6Thiazolinyl.
10. the described compound of claim 9, wherein R
7It is allyl group.
11. the described compound of claim 6, wherein R
7Be C
1-6Alkynyl.
12. the described compound of claim 11, wherein R
7It is propargyl.
13. the described compound of claim 6, wherein R
7Be C
1-6Aralkyl.
14. the described compound of claim 13, wherein R
7It is phenmethyl.
15. the described compound of claim 6, wherein R
7Be C
1-6Heteroaralkyl.
16. the described compound of claim 15, wherein R
7Be selected from 2-pyridyl, 3-pyridyl and 4-pyridyl.
17. the described compound of claim 4, wherein Q does not exist, and L is SO
2
18. the described compound of claim 17, wherein R
7Be selected from C
1-6Alkyl and C
1-6Aralkyl.
19. the described compound of claim 18, wherein R
7Be C
1-6Alkyl.
20. the described compound of claim 19, wherein R
7Be methyl.
21. the described compound of claim 18, wherein R
7Be C
1-6Aralkyl.
22. the described compound of claim 21, wherein R
7Be phenyl.
23. the described compound of claim 4, wherein L is C=O.
24. the described compound of claim 23, wherein R
7Be selected from hydrogen, C
1-6Alkyl, C
1-6Thiazolinyl, C
1-6Alkynyl, aryl, C
1-6Aralkyl, heteroaryl, C
1-6Heteroaralkyl, R
8ZA-C
1-8Alkyl-, R
11Z-C
1-8Alkyl-, (R
8O) (R
9O) P (=O) O-C
1-8Alkyl-ZAZ-C
1-8Alkyl-, (R
8O) (R
9O) P (=O) O-C
1-8Alkyl-Z-C
1-8Alkyl-, R
8ZA-C
1-8Alkyl-ZAZ-C
1-8Alkyl-, heterocyclic radical MZAZ-C
1-8Alkyl-, (R
8O) (R
9O) P (=O) O-C
1-8Alkyl-, (R
10)
2N-C
1-8Alkyl-, (R
10)
3N
+-C
1-8Alkyl-, heterocyclic radical M-, carbocylic radical M-, R
11SO
2C
1-8Alkyl-and R
11SO
2NH; Or
R
6And R
7Common is C
1-6Alkyl-Y-C
1-6Alkyl, C
1-6Alkyl-ZA-C
1-6Alkyl, A-C
1-6Alkyl-ZA-C
1-6Alkyl, A-C
1-6Alkyl-A or C
1-6Alkyl-A forms ring thus;
And each existence of Z and A is independently, is not covalent linkage.
25. the described compound of claim 24, wherein Q does not exist.
26. the described compound of claim 25, wherein R
6And R
7Be C
1-6Alkyl.
27. the described compound of claim 26, wherein R
7Be selected from ethyl, sec.-propyl, 2,2,2-trifluoroethyl and 2-(methylsulfonyl) ethyl.
28. the described compound of claim 25, wherein R
7Be C
1-6Aralkyl.
29. the described compound of claim 28, wherein R
7Be selected from 2-styroyl, phenmethyl, (4-methoxyphenyl) methyl, (4-chloro-phenyl-) methyl and (4-fluorophenyl) methyl.
30. the described compound of claim 25, wherein R
6Be C
1-6Alkyl, R
7Be aryl.
31. the described compound of claim 30, wherein R
7Be that replace or unsubstituted phenyl.
32. the described compound of claim 24, wherein Q does not exist or O, R
7Be carbocyclic ring M-.
33. the described compound of claim 32, wherein carbocyclic ring is cyclopropyl or cyclohexyl.
34. the described compound of claim 25, wherein R
7Be selected from R
8ZA-C
1-8Alkyl-, R
11Z-C
1-8Alkyl-, (R
8O) (R
9O) P (=O) O-C
1-8Alkyl-ZAZ-C
1-8Alkyl-, (R
8O) (R
9O) P (=O) O-C
1-8Alkyl-Z-C
1-8Alkyl-, R
8ZA-C
1-8Alkyl-ZAZ-C
1-8Alkyl-, heterocyclic radical MZAZ-C
1-8Alkyl-, (R
8O) (R
9O) P (=O) O-C
1-8Alkyl-, A is C=O, Z is O or NH.
35. the described compound of claim 34, wherein Z is O.
36. the described compound of claim 35, wherein R
7Be heterocyclic radical MZAZ-C
1-8Alkyl-, and heterocyclic radical is oxo dioxa cyclopentenyl or N (R
12) (R
13), R wherein
12And R
13Common is C
1-6Alkyl-Y-C
1-6Alkyl forms ring thus.
37. the described compound of claim 36, wherein R
7Be selected from (R
10)
2N-C
1-8Alkyl-and (R
10)
3N
+(CH
2)
n-, R
10Be C
1-6Alkyl.
38. the described compound of claim 25, wherein R
7Be selected from heterocyclic radical M-, heterocyclic radical is selected from morpholino, piperidino-(1-position only), Piperazino, pyrrolidino.
39. the described compound of claim 24, wherein Q is O or NH.
40. the described compound of claim 39, wherein R
6Be C
1-6Alkyl, R
7Be selected from C
1-6Alkyl, C
1-6Aralkyl and C
1-6Heteroaralkyl.
41. the described compound of claim 40, wherein R
7Be selected from methyl, ethyl, sec.-propyl, phenmethyl and (4-pyridyl) methyl.
42. the described compound of claim 24, wherein R
6And R
7Common is C
1-6Alkyl-Y-C
1- 6Alkyl, C
1-6Alkyl-ZA-C
1-6Alkyl or C
1-6Alkyl-A forms ring thus.
43. the described compound of claim 42, wherein L is C=O, and Q and Y do not exist, R
6And R
7Common is C
1-3Alkyl-Y-C
1-3Alkyl.
44. the described compound of claim 42, wherein L and Q do not exist, R
6And R
7Common is C
1-3Alkyl-Y-C
1-3Alkyl.
45. the described compound of claim 42, wherein L is C=O, and Q does not exist, and Y is selected from NH and N-C
1-6Alkyl, R
6And R
7Common is C
1-3Alkyl-Y-C
1-3Alkyl.
46. the described compound of claim 42, wherein L is C=O, and Y does not exist, R
6And R
7Common is C
1-3Alkyl-Y-C
1-3Alkyl.
47. the described compound of claim 42, wherein L and A are C=O, R
6And R
7Common is C
1-2Alkyl-ZA-C
1-2Alkyl.
48. the described compound of claim 42, wherein L and A are C=O, R
6And R
7Common is C
2-3Alkyl-A.
49. have compound or its pharmacy acceptable salt of formula II structure,
Wherein each A independently is selected from C=O, C=S and SO
2Or
When adjacent with the Z that exists, A is optional to be covalent linkage;
L does not exist or is selected from C=O, C=S and SO
2
M does not exist or is C
1-12Alkyl;
Q does not exist or is selected from O, NH and N-C
1-6Alkyl;
X is selected from O, NH and N-C
1-6Alkyl;
Y does not exist or is selected from O, NH and N-C
1-6Alkyl, S, SO, SO
2, CHOR
10And CHCO
2R
10
Each Z independently is selected from O, S, NH and N-C
1-6Alkyl; Or
When adjacent with the A that exists, Z is optional to be covalent linkage;
R
2And R
4Independently be selected from C separately
1-6Alkyl, C
1-6Hydroxyalkyl, C
1-6Alkoxyalkyl, aryl and C
1-6Aralkyl, any group are wherein randomly replaced by one or more acid amides, amine, carboxylic acid (or its salt), ester, mercaptan or thioether substituting group;
R
5Be N (R
6) LQR
7
R
6Be selected from hydrogen, OH and C
1-6Alkyl;
R
7Be selected from hydrogen, C
1-6Alkyl, C
1-6Thiazolinyl, C
1-6Alkynyl, aryl, C
1-6Aralkyl, heteroaryl, C
1-6Heteroaralkyl, R
8ZAZ-C
1-8Alkyl-, R
11Z-C
1-8Alkyl-, (R
8O) (R
9O) P (=O) O-C
1-8Alkyl-ZAZ-C
1-8Alkyl-, R
8ZAZ-C
1-8Alkyl-ZAZ-C
1-8Alkyl-, heterocyclic radical MZAZ-C
1-8Alkyl-, (R
8O) (R
9O) P (=O) O-C
1-8Alkyl-, (R
10)
2N-C
1-12Alkyl-, (R
10)
3N
+-C
1-12Alkyl-, heterocyclic radical M-, carbocylic radical M-, R
11SO
2C
1-8Alkyl-and R
11SO
2NH; Or
R
6And R
7Common is C
1-6Alkyl-Y-C
1-6Alkyl, C
1-6Alkyl-ZAZ-C
1-6Alkyl, ZAZ-C
1-6Alkyl-ZAZ-C
1-6Alkyl, ZAZ-C
1-6Alkyl-ZAZ or C
1-6Alkyl-A;
R
8And R
9Independently be selected from hydrogen, metallic cation, C
1-6Alkyl, C
1-6Thiazolinyl, C
1-6Alkynyl, aryl, heteroaryl, C
1-6Aralkyl and C
1-6Heteroaralkyl is preferably selected from hydrogen, metallic cation and C
1-6Alkyl, or R
8And R
9Common is C
1-6Alkyl forms ring thus;
Each R
10Independently be selected from hydrogen and C
1-6Alkyl is preferably C
1-6Alkyl; And
R
11Independently be selected from hydrogen, C
1-6Alkyl, C
1-6Thiazolinyl, C
1-6Alkynyl, carbocylic radical, heterocyclic radical, aryl, heteroaryl, C
1-6Aralkyl and C
1-6Heteroaralkyl, condition are to work as R
6Be H or CH
3, and Q is not when existing, LR
7Be not hydrogen, unsubstituted C
1-6Alkyl C=O, amino acid whose another chain, tertbutyloxycarbonyl (Boc), benzoyl (Bz), fluorenes-9-base methoxycarbonyl (Fmoc), trityl group (trityl), carbobenzoxy-(Cbz) (Cbz), trichloro-ethoxycarbonyl (Troc); Replace or unsubstituted aryl or heteroaryl; And
Under any situation that has a sequence ZAZ, having a member in this sequence at least must not be covalent linkage.
50. have compound or its pharmacy acceptable salt of formula (III) structure,
Wherein X is O, NH or N-alkyl, is preferably O;
R
1, R
2, R
3And R
4Independently be selected from the group of hydrogen and formula IV, restricted condition is R
1, R
2, R
3And R
4In at least one is the group of formula IV;
R
5, R
6, R
7And R
8Independently be selected from C
1-6Alkyl, C
1-6Hydroxyalkyl, C
1-6Alkoxyalkyl, aryl and C
1-6Aralkyl, wherein each group randomly is selected from the group replacement of acid amides, amine, carboxylic acid or its pharmacy acceptable salt, carboxylicesters, mercaptan or thioether;
R
9Be amino acid whose another chain, hydrogen, C
1-6Acyl group, protecting group, replacement or unsubstituted aryl or that replace or unsubstituted heteroaryl, wherein substituting group comprises halogen, carbonyl, nitro, hydroxyl, aryl and C
1-5Alkyl;
R
10And R
11Independently be selected from hydrogen and C
1-6Alkyl, or R
10And R
11Form the carbocyclic ring or the heterocycle of 3-6 unit together;
R
12And R
13Independently be selected from hydrogen, metallic cation, C
1-6Alkyl and C
1-6Aralkyl, or R
12And R
13Common expression C
1-6Alkyl forms ring thus; And
L does not exist or is selected from-CO
2Or-C (=S) O.
51. a pharmaceutical composition comprises claim 1 or 50 described compounds and pharmaceutically acceptable carrier.
52. a method that suppresses N-end nucleophilic lytic enzyme comprises the described compound of the claim 1 for the treatment of significant quantity.
53. a method for the treatment of inflammation comprises the described compound of the claim 1 for the treatment of significant quantity.
54. one kind is suppressed or alleviates the method that HIV infects, comprises the described compound of the claim 1 for the treatment of significant quantity.
55. a method for the treatment of neurodegenerative disease comprises the described compound of the claim 1 for the treatment of significant quantity.
56. a method for the treatment of muscular dystrophy comprises the described compound of the claim 1 for the treatment of significant quantity.
57. a treatment method for cancer comprises the described compound of the claim 1 for the treatment of significant quantity.
58. a method for the treatment of chronic infectious disease comprises the described compound of the claim 1 for the treatment of significant quantity.
59. a method for the treatment of heating comprises the described compound of the claim 1 for the treatment of significant quantity.
60. the method for the immune-related illness of treatment comprises the described compound of the claim 1 for the treatment of significant quantity.
61. a method for the treatment of denervation or nerve injury comprises the described compound of the claim 1 for the treatment of significant quantity.
62. a method that influences viral gene expression level in the individuality comprises the described compound of the claim 1 for the treatment of significant quantity.
63. a method that changes the antigen peptide kind that proteasome produces in the organism comprises the described compound of the claim 1 for the treatment of significant quantity.
Applications Claiming Priority (14)
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| US56234004P | 2004-04-15 | 2004-04-15 | |
| US60/562340 | 2004-04-15 | ||
| US56909604P | 2004-05-07 | 2004-05-07 | |
| US60/569096 | 2004-05-07 | ||
| US59940104P | 2004-08-06 | 2004-08-06 | |
| US60/599401 | 2004-08-06 | ||
| US61015904P | 2004-09-14 | 2004-09-14 | |
| US61000104P | 2004-09-14 | 2004-09-14 | |
| US61000204P | 2004-09-14 | 2004-09-14 | |
| US60/610159 | 2004-09-14 | ||
| US60/610002 | 2004-09-14 | ||
| US60/610001 | 2004-09-14 | ||
| US62057304P | 2004-10-20 | 2004-10-20 | |
| US60/620573 | 2004-10-20 |
Related Parent Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN200580019845.4A Division CN101006098B (en) | 2004-04-15 | 2005-04-14 | Compounds for proteasome enzyme inhibition |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN102174076A true CN102174076A (en) | 2011-09-07 |
Family
ID=34965899
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201110037869XA Pending CN102174076A (en) | 2004-04-15 | 2005-04-14 | Compounds for proteasome enzyme inhibition |
| CN201310512372.8A Pending CN103554222A (en) | 2004-04-15 | 2005-04-14 | Compounds for enzyme inhibition |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201310512372.8A Pending CN103554222A (en) | 2004-04-15 | 2005-04-14 | Compounds for enzyme inhibition |
Country Status (17)
| Country | Link |
|---|---|
| US (9) | US8129346B2 (en) |
| EP (1) | EP1745064B1 (en) |
| JP (3) | JP5616569B2 (en) |
| CN (2) | CN102174076A (en) |
| AT (1) | ATE494298T1 (en) |
| AU (1) | AU2005238445B2 (en) |
| BR (1) | BRPI0509879A (en) |
| CA (1) | CA2562411A1 (en) |
| CY (1) | CY1117244T1 (en) |
| DE (1) | DE602005025750D1 (en) |
| DK (1) | DK1745064T3 (en) |
| HK (1) | HK1097860A1 (en) |
| IL (3) | IL178400A (en) |
| PL (1) | PL1745064T3 (en) |
| PT (1) | PT1745064E (en) |
| SG (2) | SG152239A1 (en) |
| WO (1) | WO2005105827A2 (en) |
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2005
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- 2005-04-14 EP EP05735686A patent/EP1745064B1/en active Active
- 2005-04-14 BR BRPI0509879-3A patent/BRPI0509879A/en not_active Application Discontinuation
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- 2005-04-14 AT AT05735686T patent/ATE494298T1/en active
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- 2005-04-14 CA CA002562411A patent/CA2562411A1/en not_active Abandoned
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- 2012-03-02 US US13/411,044 patent/US20120277146A1/en not_active Abandoned
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